Pyrimidinedione compounds

ABSTRACT

Provided are novel pyrimidine dione compounds and pharmaceutically acceptable salts thereof, that are useful for the treatment of hypertrophic cardiomyopathy (HCM) and conditions associated with left ventricular hypertrophy or diastolic dysfunction. The synthesis and characterization of the compounds and pharmaceutically acceptable salts thereof, are described, as well as methods for treating HCM and other forms of heart disease.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/409,369, filed on Jan. 18, 2017, which is a continuation of U.S.patent application Ser. No. 14/883,152, filed on Oct. 14, 2015, which isa division of U.S. patent application Ser. No. 14/309,381, filed on Jun.19, 2014, all of which are claiming the benefit under 35 U.S.C. § 119(e)of U.S. Provisional Application No. 61/838,088 filed Jun. 21, 2013, andU.S. Provisional Application No. 61/939,655 filed Feb. 13, 2014, andU.S. Provisional Application No. 61/981,366 filed Apr. 18, 2014, each ofwhich is herein incorporated by reference in its entirety.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

NOT APPLICABLE

BACKGROUND OF THE INVENTION

Genetic (heritable) hypertrophic cardiomyopathy (HCM) comprises a groupof highly penetrant, monogenic, autosomal dominant myocardial diseases.HCM is caused by one or more of over 1,000 known point mutations in anyone of the structural protein genes contributing to the functional unitof myocardium, the sarcomere. About 1 in 500 individuals in the generalpopulation are found to have left ventricular hypertrophy unexplained byother known causes (e.g., hypertension or valvular disease), and many ofthese can be shown to have HCM, once other heritable (e.g., lysosomalstorage diseases), metabolic, or infiltrative causes have been excluded.

Sarcomere gene mutations that cause HCM are highly penetrant, but thereis wide variability in clinical severity and clinical course. Somegenotypes are associated with a more malignant course, but there isconsiderable variability between and even within families carrying thesame mutation. Sex differences have also been noted, with male patientsgenerally more severely affected than female patients. While manypatients with HCM report minimal or no symptoms for extended periods oftime, HCM is a progressive disease with a significant cumulative burdenof morbidity. Symptoms of effort intolerance predominate, and can beexacerbated by exercise and other maneuvers that increase heart rateand/or decrease preload. As with many other disorders, symptoms tend toworsen with age. By far the most prevalent clinical burden for patientswith HCM is exertional dyspnea, which limits their activities of dailyliving and can be debilitating.

Patients with HCM are often symptomatic in the absence of documentedhemodynamic abnormalities like left ventricular outflow tractobstruction (with or without mitral regurgitation). Patients' symptomsof exertional dyspnea can rapidly worsen with the onset of atrialfibrillation, a common complication of HCM that can precipitate acutepulmonary edema that increases the risk of systemic arterialthromboembolic disease, including stroke. Other adverse eventsassociated with HCM include intolerance of hypovolemia or hypervolemia,and syncope. Concomitant coronary artery disease may confer a higherrisk of acute coronary syndromes than in patients without HCM. Suddencardiac death (SCD) in patients with HCM is both uncommon and difficultto predict but is a leading cause of non-traumatic death in youngadults. For survivors of SCD, ICD placement is standard practice, and inother HCM patients risk profiling, while imprecise, is used to identifythose for whom ICD placement for primary prevention is deemed prudent.

Medical therapy for HCM is limited to the treatment of symptoms and doesnot address the fundamental, underlying cause of disease—disruptions innormal sarcomere function. Currently available therapies are variablyeffective in alleviating symptoms but typically show decreased efficacywith increasing disease duration. Patients are thus empirically managedwith beta-blockers, non-dihydropyridine calcium channel blockers, and/ordisopyramide. None of these agents carry labeled indications fortreating HCM, and essentially no rigorous clinical trial evidence isavailable to guide their use. Compounding this unfortunate situation isthe fact that no new medical therapies for HCM have been identified formany years. For patients with hemodynamically significant outflow tractobstruction (resting gradient >30 mmHg), in appropriately selectedpatients surgical myectomy or alcohol septal ablation is usuallyrequired to alleviate the hemodynamic obstruction. Provided are newtherapeutic agents and methods that remedy the long-felt need forimproved treatment of HCM and related cardiac disorders.

BRIEF SUMMARY OF THE INVENTION

In one aspect, provided is a compound having the formula:

or a pharmaceutically acceptable salt thereof. In some embodiments, theabove formula, R¹ is a member selected from C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl-C₁-C₄ alkyl, 4- to 7-memberedheterocycloalkyl, phenyl, phenyl-C₁-C₄ alkyl, 5- to 6-memberedheteroaryl and 5- to 6-membered heteroaryl-C₁-C₄ alkyl, wherein each R¹is optionally substituted with from 1-3 R^(a); R² is a member selectedfrom phenyl, phenyl-C₁-C₄ alkyl, 5- to 6-membered heteroaryl and 5- to6-membered heteroaryl-C₁-C₄ alkyl, wherein each R² is optionallysubstituted with from 1-5 R^(b); R³ is a member selected from C₁-C₄alkyl, C₃-C₄ cycloalkyl, and 4- to 7-membered heterocycloalkyl whereineach R³ is optionally substituted with from 1-3 R^(c); R⁴ is H; X is amember selected from H and halo, and in some embodiments X is selectedfrom H and F. Each R^(a),when present, is independently selected fromhalo, CN, hydroxyl, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenyl,phenyl-C₁-C₄ alkyl, phenyl-C₁-C₄ alkoxy, phenoxy, —COR^(a1), —CO₂R^(a1),—SO₂R^(a1), —SO₂NR_(a1)R^(a2), and —CONR^(a1)R^(a2), wherein each R^(a1)and R^(a2) is independently selected from H, C₁-C₄ alkyl and phenyl, oroptionally R^(a1) and R^(a2) when attached to a nitrogen atom arecombined to form a 4- to 6-membered ring. Similarly, each R^(b), whenpresent, is independently selected from halo, CN, hydroxyl, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenoxy, phenyl-C₁-C₄ alkoxy,methylenedioxy, difluoromethylenedioxy, —COR^(b1), —CO₂R^(b1),—SO₂R^(b1), —SO₂NR^(b1)R^(b2), CONR^(b1)R^(b2), NR^(b1)R^(b2), 5- to6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionallysubstituted with oxo, wherein each R^(b1) and R^(b2) is independentlyselected from H and C₁-C₄ alkyl or optionally R^(b1) and R^(b2) whenattached to a nitrogen atom are combined to form a 4- to 6-memberedring; and each R^(c), when present, is independently selected from halo,hydroxyl and C₁-C₂ alkoxy.

In another aspect, provided is a pharmaceutical composition containing acompound or or pharmaceutically acceptable salt described herein and apharmaceutically acceptable excipient.

In another aspect, provided is a method of treating hypertrophiccardiomyopathy (HCM) or a cardiac disorder having one or morepathophysiological features associated with HCM. The method includesadministering to a subject in need thereof an effective amount of acompound or pharmaceutically acceptable salt described herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a schematic route for the synthesis of the compounds orpharmaceutically acceptable salts described herein (FIG. 1A) and a routefor the preparation of chiral amines (FIG. 1B).

DETAILED DESCRIPTION OF THE INVENTION I. General

A series of pyrimidine dione compounds and pharmaceutically acceptablesalts thereof has been found to reduce excess contractility inhypercontractile states and/or promote cardiac relaxation in hearts withdiastolic dysfunction by stabilizing the conformation of beta cardiacmyosin post-ATP hydrolysis but prior to strongly binding the actinfilament and releasing phosphate, thus reducing the proportion of myosinmolecules that are available to participate in the “powerstroke” portionof the muscle contraction cycle. As such, the compounds can improvecardiac elasticity, reduce dynamic and/or static left ventricularoutflow obstruction, improve diastolic left ventricular relaxation,reduce left ventricular diastolic (filling) pressures, reduce functionalmitral regurgitation, and/or reduce left atrial and pulmonary capillarywedge pressures in patients with HCM helping overcome the debilitatingexertional dyspnea and/or symptoms referable to left ventricular outflowobstruction (presyncope or syncope) that often accompanies the disease.The compounds can also be used to treat other cardiac disorders.

II. Definitions

As used herein, the term “alkyl” refers to a straight or branched,saturated, aliphatic radical having the number of carbon atomsindicated. Alkyl can include any number of carbons, such as C₁₋₂, C₁₋₃,C₁₋₄, C₁₋₅, C₁₋₆, C₁₋₇, C₁₋₈, C₂₋₃, C₂₋₄, C₂₋₅, C₂₋₆, C₃₋₄, C₃₋₅, C₃₋₆,C₄₋₅, C₄₋₆ and C₅₋₆. For example, C₁₋₆ alkyl includes, but is notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl can refer toalkyl groups having up to 20 carbons atoms, such as, but not limited toheptyl, octyl, nonyl, decyl, etc. Unless stated otherwise, alkyl groupsare unsubstituted. A “substituted alkyl” group can be substituted withone or more moieties selected from halo, hydroxy, amino, alkylamino,nitro, cyano, and alkoxy.

As used herein, the term “cycloalkyl” refers to a saturated or partiallyunsaturated, monocyclic, fused bicyclic or bridged polycyclic ringassembly containing from 3 to 12 ring atoms, or the number of atomsindicated. Cycloalkyl can include any number of carbons, such as C₃₋₆,C₄₋₆, C₅₋₆, C₃₋₈, C₄₋₈, C₅₋₈, and C₆₋₈. Saturated monocyclic cycloalkylrings include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkylrings include, for example, norbornane, [2.2.2]bicyclooctane,decahydronaphthalene and adamantane. Cycloalkyl groups can also bepartially unsaturated, having one or more double bonds in the ring.Representative cycloalkyl groups that are partially unsaturated include,but are not limited to, cyclobutene, cyclopentene, cyclohexene,cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene,cyclooctene, cyclooctadiene (1,3-, 1,4- and 1,5-isomers), norbornene,and norbornadiene. Unless otherwise stated, cycloalkyl groups areunsubstituted. A “substituted cycloalkyl” group can be substituted withone or more moieties selected from halo, hydroxy, amino, alkylamino,nitro, cyano, and alkoxy.

As used herein, the term “heterocycloalkyl” refers to a saturated ringsystem having from 3 to 12 ring members and from 1 to 4 heteroatomsselected from N, O and S. Additional heteroatoms including, but notlimited to, B, Al, Si and P can also be present in a heterocycloalkylgroup. The heteroatoms can be oxidized to form moieties such as, but notlimited to, —S(O)— and —S(O)₂—. Heterocycloalkyl groups can include anynumber of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, or 4 to 7 ringmembers. Any suitable number of heteroatoms can be included in theheterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to4, 2 to 3, 2 to 4, or 3 to 4. Examples of heterocycloalkyl groupsinclude, but are not limited to, aziridine, azetidine, pyrrolidine,piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine,piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane,tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane,thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran),oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane,dithiolane, morpholine, thiomorpholine, dioxane, or dithiane.Heterocycloalkyl groups are unsubstituted, but can be described, in someembodiments as substituted. “Substituted heterocycloalkyl” groups can besubstituted with one or more moieties selected from halo, hydroxy,amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term “heteroaryl” refers to a monocyclic or fusedbicyclic or tricyclic aromatic ring assembly containing 5 to 16 ringatoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, Oor S. Additional heteroatoms including, but not limited to, B, Al, Siand P can also be present in a heteroaryl group. The heteroatoms can beoxidized to form moieties such as, but not limited to, —S(O)— and—S(O)₂—. Heteroaryl groups can include any number of ring atoms, suchas, 5 to 6, 5 to 8, 6 to 8, 5 to 9, 5 to 10, 5 to 11, or 5 to 12 ringmembers. Any suitable number of heteroatoms can be included in theheteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4,1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups canhave from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring membersand from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3heteroatoms. Examples of heteroaryl groups include, but are not limitedto, pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole,pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, andisoxazole. Heteroaryl groups are unsubstituted, but can be described, insome embodiments as substituted. “Substituted heteroaryl” groups can besubstituted with one or more moieties selected from halo, hydroxy,amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the term “alkoxy” refers to an alkyl group having anoxygen atom that connects the alkyl group to the point of attachment:i.e., alkyl-O—. As for the alkyl portion, alkoxy groups can have anysuitable number of carbon atoms, such as C₁₋₆ or C₁₋₄. Alkoxy groupsinclude, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy,2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, etc.Alkoxy groups are unsubstituted, but can be described, in someembodiments as substituted. “Substituted alkoxy” groups can besubstituted with one or more moieties selected from halo, hydroxy,amino, alkylamino, nitro, cyano, and alkoxy.

As used herein, the terms “halo” and “halogen” refer to fluorine,chlorine, bromine and iodine.

As used herein, the term “pharmaceutically acceptable” refers to asubstance that is compatible with a compound or salt as describedherein, as well as with any other ingredients with which the compound isformulated. Furthermore, a pharmaceutically acceptable substance is notdeleterious to the recipient of the substance.

As used herein, the term “salt” refers to an acid or base salt of acompound described herein. Pharmaceutically acceptable salts can bederived, for example, from mineral acids (hydrochloric acid, hydrobromicacid, phosphoric acid, and the like), organic acids (acetic acid,propionic acid, glutamic acid, citric acid and the like), and quaternaryammonium ions. It is understood that the pharmaceutically acceptablesalts are non-toxic. Additional information on suitable pharmaceuticallyacceptable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa., 1985, which isincorporated herein by reference. The neutral form of a compound may beregenerated by contacting the salt with a base or acid and isolating theparent compound in the conventional manner.

As used herein, the term “pharmaceutical composition” refers to aproduct comprising a compound or pharmaceutically acceptable saltdescribed herein, an excipient as defined herein, and other optionalingredients in specified amounts, as well as any product which resultsdirectly or indirectly from combination of the specified ingredients inthe specified amounts.

As used herein, the term “excipient” refers to a substance that aids theadministration of an active agent to a subject. Pharmaceuticalexcipients include, but are not limited to, binders, fillers,disintegrants, lubricants, coatings, sweeteners, flavors and colors. Oneof skill in the art will recognize that other excipients can be useful.

As used herein, the terms “treat,” “treating” and “treatment” refer toany indicia of success in the treatment or amelioration of a pathology,injury, condition, or symptom related to hypertrophic cardiomyopathy,including any objective or subjective parameter such as abatement;remission; diminishing of symptoms; making the pathology, injury,condition, or symptom more tolerable to the patient; decreasing thefrequency or duration of the pathology, injury, condition, or symptom;or, in some situations, preventing the onset of the pathology, injury,condition, or symptom. Treatment or amelioration can be based on anyobjective or subjective parameter; including, e.g., the result of aphysical examination.

III. Compounds and Pharmaceutically Acceptable Salts Thereof

In one aspect, provided is a compound having the formula:

or a pharmaceutically acceptable salt thereof

In the above formula, R¹ is a member selected from C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl-C₁-C₄ alkyl, 4- to 7-memberedheterocycloalkyl, phenyl, phenyl-C₁-C₄ alkyl, 5- to 6-memberedheteroaryl and 5- to 6-membered heteroaryl-C₁-C₄ alkyl, wherein each R¹is optionally substituted with from 1-3 R^(a); R² is a member selectedfrom phenyl, phenyl-C₁-C₄ alkyl, 5- to 6-membered heteroaryl and 5- to6-membered heteroaryl-C₁-C₄ alkyl, wherein each R² is optionallysubstituted with from 1-5 R^(b); R³ is a member selected from C₁-C₄alkyl, C₃-C₄ cycloalkyl, and 4- to 7-membered heterocycloalkyl whereineach R³ is optionally substituted with from 1-3 R^(c); R⁴ is H; X is amember selected from H and halo, and in selected embodiments is selectedfrom H and F. Each R^(a), when present, is independently selected fromhalo, CN, hydroxyl, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenyl,phenyl-C₁-C₄ alkyl, phenyl-C₁-C₄ alkoxy, phenoxy, —COR^(a1), —CO₂R^(a1),—SO₂R^(a1), —SO₂NR_(a1)R^(a2), and —CONR^(a1)R^(a2), wherein each R^(a1)and R^(a2) is independently selected from H, C₁-C₄ alkyl and phenyl, oroptionally R^(a1) and R^(a2) when attached to a nitrogen atom arecombined to form a 4- to 6-membered ring. Similarly, each R^(b), whenpresent, is independently selected from halo, CN, hydroxyl, C₁-C₄ alkyl,C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenoxy, phenyl-C₁-C₄ alkoxy,methylenedioxy, difluoromethylenedioxy, —COR^(b1), —CO₂R^(b1),—SO₂R^(b1), —SO₂NR^(b1)R^(b2), CON^(b1)R^(b2), NR^(b1)R^(b2), 5- to6-membered heteroaryl, and 5- to 6-membered heterocyclyl optionallysubstituted with oxo, wherein each R^(b1) and R^(b2) is independentlyselected from H and C₁-C₄ alkyl or optionally R^(b1) and R^(b2) whenattached to a nitrogen atom are combined to form a 4- to 6-memberedring; and each R^(c), when present, is independently selected from halo,hydroxyl and C₁-C₂ alkoxy.

In some embodiments, R¹ is selected from C₁-C₈ alkyl, C₃-C₈ cycloalkyl,4- to 7-membered heterocycloalkyl, phenyl, or 5- to 6-memberedheteroaryl, wherein each R¹ is optionally substituted with from 1-3R^(a). R² is phenyl, which is optionally substituted with from 1-5R^(b). R³ is selected from C₁-C₄ alkyl, C₃-C₄ cycloalkyl, or 4- to7-membered heterocycloalkyl, wherein each R³ is optionally substitutedwith from 1-2 R^(c). R⁴ is H, and X is H or F. In some embodiments, eachR^(a), when present, is independently halo, CN, C₁-C₄ alkyl, C₁-C₄alkoxy, —COR^(a1), —CO₂R^(a1), —SO₂R^(a1), —SO₂NR^(a1)R^(a2), or—CONR^(a1)R^(a2), wherein each R^(a1) and R^(a2) is independently H orC₁-C₄ alkyl. Alternatively, R^(a1) and R^(a2), when attached to anitrogen atom, are optionally combined to form a 4- to 6-membered ring.Each R^(b), when present, is independently halo, CN, C₁-C₄ alkyl, C₁-C₄alkoxy, —COR^(b1), —CO_(b2)R^(b1), —SO₂R^(b1), —SO₂NR^(b1)R^(b2),CONR^(b1)R^(b2), NR^(b1)R^(b2), 5- to 6-membered heteroaryl, or 5- to6-membered heterocyclyl optionally substituted with oxo, wherein eachR^(b1) and R^(b2) is independently H or C₁-C₄ alkyl. Alternatively,R^(b1) and R^(b2), when attached to a nitrogen atom, are optionallycombined to form a 4- to 6-membered ring. Each R^(c), when present, isindependently halo or C₁-C₂ alkoxy.

In some embodiments, X is H.

In some embodiments, R¹ is C₃-C₄ alkyl, C₃-C₅ cycloalkyl, or 4- to6-membered heterocycloalkyl, wherein each R¹ is optionally substitutedwith from 1-2 R^(a).

In some embodiments, R¹ is phenyl or 5- to 6-membered heteroaryl,wherein each R¹ is optionally substituted with from 1-3 R^(a).

In some embodiments, R¹ is C₃-C₄ alkyl, C₃-C₅ cycloalkyl, or 4- to6-membered heterocycloalkyl.

In some embodiments, R¹ is 4- to 6-membered heterocycloalkyl, optionallysubstituted with from 1-2 R^(a) selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,—COR^(a1), —CO₂R^(a1), —SO₂R^(a1), —SO₂NR^(a1)R^(a2), and—CONR^(a1)R^(a2), wherein each R^(a1) and R^(a2) is independently H orC₁-C₄ alkyl.

In some embodiments, R¹ is cyclobutyl, isopropyl, isobutyl,1-methoxypropan-2-yl, cyclopentyl, cyclohexyl, 4-tetrahydropyranyl,1-(methylsulfonyl)piperidin-4-yl, 1-(methoxycarbonyl)piperidin-4-yl,4,4-difluorocyclohexyl, phenyl, 2-pyridyl, 3-pyridyl, 3-isoxazolyl,5-isoxazolyl, or 1-methyl-3-pyrazolyl.

In some embodiments, R² is optionally substituted with from 1-2 R^(b).

In some embodiments, R² is phenyl, 3-methylphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl,3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, or3-(1,2,4-triazol-1-yl)phenyl.

In some embodiments, R³ is C₁-C₄ alkyl, C₁-C₄ alkoxyalkyl, or C₃-C₄cycloalkyl.

In some embodiments, R³ is methyl, ethyl, propyl, cyclopropyl,cyclobutyl or 2-methoxymethyl.

In some embodiments, R³ is methyl.

The compounds or pharmaceutically acceptable salts described herein canhave any combination of the R¹, R², R³, R⁴, R^(a), R^(a1), R^(a2),R^(b), R^(b1), R^(b2), R^(c), and X groups recited above. Selectedembodiments recited for R², for example, can be combined with any of theselected embodiments recited for R¹ which, in turn, can be combined withany of the selected embodiments recited for R³.

In some embodiments, for example, R¹ is C₃-C₈ alkyl; R³ is C₃-C₄cycloalkyl or 4- to 7-membered heterocycloalkyl; and R² is phenyl. Inother embodiments, R¹ is 4- to 7-membered heterocycloalkyl or 5- to6-membered heteroaryl which is optionally substituted with C₁-C₄ alkyl,—CO₂R^(a1), —SO_(2NR) ^(a1)R^(a2), or —SO₂R^(a1); R³ is C₃-C₄ cycloalkylor 4- to 7-membered heterocycloalkyl; and R² is phenyl. In still otherembodiments, R¹ is C₃-C₈ cycloalkyl or phenyl, R³ is C₃-C₄ cycloalkyl or4- to 7-membered heterocycloalkyl; and R² is phenyl.

In other embodiments, R¹ is C₃-C₈ alkyl; R³ is C₁-C₄ alkyl; and R² isphenyl. In yet other embodiments, R¹ is 4- to 7-memberedheterocycloalkyl or 5- to 6-membered heteroaryl which is optionallysubstituted with C₁-C₄ alkyl, —CO₂R^(a1), or —SO₂R^(a1); R³ is C₁-C₄alkyl; and R² is phenyl. In still other embodiments, R¹ is C₃-C₈cycloalkyl or phenyl; R³ is C₁-C₄ alkyl; and R² is phenyl.

In some embodiments, R¹ is C₃-C₈ alkyl; R³ is C₃-C₄ cycloalkyl or 4- to7-membered heterocycloalkyl; and R² is phenyl substituted with 1-2 C₁-C₄alkoxy or halo. In still other embodiments, R¹ is 4- to 7-memberedheterocycloalkyl or 5- to 6-membered heteroaryl which is optionallysubstituted with C₁-C₄ alkyl, —CO₂R^(a1), or —SO₂R^(a1); R³ is C₃-C₄cycloalkyl or 4- to 7-membered heterocycloalkyl; and R² is phenylsubstituted with 1-2 C₁-C₄ alkoxy or halo. In yet other embodiments, R¹is C₃-C₈ cycloalkyl or phenyl; R³ is C₃-C₄ cycloalkyl or 4- to7-membered heterocycloalkyl; and R² is phenyl substituted with 1-2 C₁-C₄alkoxy or halo.

In some embodiments, R¹ is C₃-C₈ alkyl; R³ is C₁-C₄ alkyl; and R² isphenyl substituted with 1-2 C₁-C₄ alkoxy or halo. In other embodiments,R¹ is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroarylwhich is optionally substituted with C₁-C₄ alkyl, —CO₂R^(a1), or—SO₂R^(a1); R³ is C₁-C₄ alkyl; and R² is phenyl substituted with 1-2C₁-C₄ alkoxy or halo. In other embodiments, R¹ is C₃-C₈ cycloalkyl orphenyl; R³ is C₁-C₄ alkyl; and R² is phenyl substituted with 1-2 C₁-C₄alkoxy or halo.

In some embodiments, R¹ is C₃-C₈ alkyl; R³ is C₃-C₄ cycloalkyl or 4- to7-membered heterocycloalkyl; and R² is phenyl substituted with 5- to6-membered heteroaryl or 5- to 6-membered heterocyclyl optionallysubstituted with oxo. In other embodiments, R¹ is 4- to 7-memberedheterocycloalkyl or 5- to 6-membered heteroaryl which is optionallysubstituted with C₁-C₄ alkyl, —CO₂R^(a1), or —SO₂R^(a1); R³ is C₃-C₄c_(y)cloalkyl or 4- to 7-membered heterocycloalkyl; and R² is phenylsubstituted with 5- to 6-membered heteroaryl or 5- to 6-memberedheterocyclyl optionally substituted with oxo. In other embodiments, R¹is C₃-C₈ cycloalkyl or phenyl, R³ is C₃-C₄ cycloalkyl or 4- to7-membered heterocycloalkyl; and R² is phenyl substituted with 5- to6-membered heteroaryl or 5- to 6-membered heterocyclyl optionallysubstituted with oxo.

In some embodiments, R¹ is C₃-C₈ alkyl; R³ is C₁-C₄ alkyl; and R² isphenyl substituted with 5- to 6-membered heteroaryl or 5- to 6-memberedheterocyclyl optionally substituted with oxo. In other embodiments, R¹is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroarylwhich is optionally substituted with C₁-C₄ alkyl, —CO₂R^(a1), or—SO₂R^(a1); R³ is C₁-C₄ alkyl; and R² is phenyl substituted with 5- to6-membered heteroaryl or 5- to 6-membered heterocyclyl optionallysubstituted with oxo. In other embodiments, R¹ is C₃-C₈ cycloalkyl orphenyl; R³ is C₁-C₄ alkyl; and R² is phenyl substituted with 5- to6-membered heteroaryl or 5- to 6-membered heterocyclyl optionallysubstituted with oxo.

In some embodiments, R¹ is C₃-C₈ alkyl; R³ is C₃-C₄ cycloalkyl or 4- to7-membered heterocycloalkyl; and R² is phenyl substituted with CN, C₁-C₄alkyl, —COR^(b1), —CO₂R^(b1), —SO₂R^(b1), —SO₂NR^(b1)R^(b2),CONR^(b1)R^(b2), or NR^(b1)R^(b2). In other embodiments, R¹ is 4- to7-membered heterocycloalkyl or 5- to 6-membered heteroaryl which isoptionally substituted with C₁-C₄ alkyl, —CO₂R^(a1); or —SO₂R^(a1); R³is C₃-C₄ cycloalkyl or 4- to 7-membered heterocycloalkyl; and R² isphenyl substituted with CN, C₁-C₄ alkyl, —COR^(b1), —CO₂R_(b1),—SO₂R_(b1), CONR^(b1)R^(b2), or NR^(b1)R^(b2). In other embodiments, R¹is C₃-C₈ cycloalkyl or phenyl; R³ is C₃-C₄ cycloalkyl or 4- to7-membered heterocycloalkyl; and R² is phenyl substituted with CN, C₁-C₄alkyl, —COR^(b1), —CO₂R^(b1), —SO₂R^(b1), CONR^(b1)R^(b2), orNR^(b1)R^(b2).

In some embodiments, R¹ is C₃-C₈ alkyl; R³ is C₁-C₄ alkyl; and R² isphenyl substituted with CN, C₁-C₄ alkyl, —COR^(b1), —CO₂R^(b1),—SO₂R^(b1), CONR^(b1)R^(b2), or NR^(b1)R^(b2). In other embodiments, R¹is 4- to 7-membered heterocycloalkyl or 5- to 6-membered heteroarylwhich is optionally substituted with C₁-C₄ alkyl, —CO₂R^(a1), or—SO₂R^(a1); R³ is C₁-C₄ alkyl; and R² is phenyl substituted with CN,C₁-C₄ alkyl, —COR^(b1), —CO₂R^(b1), —SO₂R^(b1), CONR^(b1)R^(b2), orNR^(b1)R^(b2). In other embodiments, R¹ is C₃-C₈ cycloalkyl or phenyl;R³ is C₁-C₄ alkyl; and R² is phenyl substituted with CN, C₁-C₄ alkyl,—COR^(b1), —CO₂R^(b1), —SO₂R_(b1), CONR^(b1)R^(b2), NR^(b1)R^(b2), or—CONR^(a1)R^(a2).

In some embodiments, R¹ is isopropyl; R² is optionally substituted with1-2 R^(b); and R³ is methyl.

In some embodiments, R¹ is 4- to 6-membered heterocycloalkyl, optionallysubstituted with from 1-2 R^(a) selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,—COR^(a1), —CO₂R^(a1), —SO₂R^(a1), —SO₂NR^(a1) R^(a2), and—CONR^(a1)R^(a2), wherein each R^(a1) and R^(a2) can independently be Hor C₁-C₄ alkyl; R² is optionally substituted with 1-2 R^(b); and R³ ismethyl.

In some embodiments, R¹ is phenyl or 5- to 6-membered heteroaryl,wherein each R¹ is optionally substituted with from 1-3 Ra; R² isoptionally substituted with from 1-2 R^(b); and R³ is methyl.

X can be H in any of the embodiments set forth above. In otherembodiments, X can be F in any of the embodiments set forth above. Stillfurther, compounds provided herein with an identified stereochemistry(indicated as R or S, or with dashed or wedge bond designations) will beunderstood by one of skill in the art to be substantially free of otherisomers (e.g., at least 80%, 90%, 95% up to 100% free of the otherisomer).

In some embodiments, the compound is selected from:

-   (S)-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-5-fluoro-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-5-bromo-3-isopropyl-6-((1phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((cyclopropyl(3-methoxyphenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-methoxyphenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione;-   6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   methyl    (S)-4-(2,6-dioxo-4-((1-phenylethyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)piperidine-1-carboxylate;-   3-((R)-sec-butyl)-6-(((S)-1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-phenylethyl)amino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(isoxazol-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-(1H-pyrazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(2-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-5-methyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(2-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(4-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-5-fluoro-3-isopropyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-5-fluoro-6-((1-(3-fluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-5-fluoro-3-isopropyl-6-((1-(3-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(2,5-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-bromophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-ethyl-6-((1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-cyclopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-phenylethyl)amino)-3-(pyridin-2-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(1-methyl-1H-pyrazol-3-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(isoxazol-5-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-(1H-1,2,4-triazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(3-(2-methyl-1H-imidazol-1-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(3-(2-oxooxazolidin-3-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-cyclohexyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-phenyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-ethyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-methyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (R)-3-isopropyl-6-((2,2,2-trifluoro-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   3-((R)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-2-(1-((1-isopropyl-2,6-dioxo-1,2,3,6-tetrahydropyrimidin-4-yl)amino)ethyl)benzonitrile-   (S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(2,6-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(4-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-(1H-imidazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-phenylethyl)amino)-3-(pyridazin-4-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-4-((1-phenylethyl)amino)-2H-[1,5′-bipyrimidine]-2,6(3H)-dione;-   (S)-6-((1-phenylethyl)amino)-3-(pyrazin-2-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(pyridin-3-yl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(1-methyl-1H-pyrazol-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-phenylbutyl)amino)pyrimidine-2,4(1H,3H)-dione;-   6-(((S)-1-phenylethyl)amino)-3-((R)-tetrahydro-2H-pyran-3-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-cyclopentyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((2-methyl-1-phenylpropyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(4,4-difluorocyclohexyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(pentan-3-yl)-6-((1-phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(1-benzoylpiperidin-4-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-i    sopropyl-6-((4-phenylbutan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione;-   methyl    (S)-2-(2,6-dioxo-4-((1-phenylethyl)amino)-3,6-dihydropyrimidin-1(2H)-yl)acetate-   (S)-3-i    sopropyl-6-((1-phenylpropan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione;-   3-((S)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   3-((S)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (R)-6-((2-hydroxy-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   6-(((S)-1-phenylethyl)amino)-3-((R)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione;-   6-(((S)-1-phenylethyl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione;-   6-(((S)-1-phenylethyl)amino)-3-(4,4,4-trifluorobutan-2-yl)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-phenylethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(tert-butyl)-6-((1-phenyl    ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(2-methoxyethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   6-(((S)-1-phenylpropyl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione;-   3-((R)-1-cyclopropylethyl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   3-((S)-1-cyclopropylethyl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(benzo[d]    [1,3]dioxol-5-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(benzo[d]    [1,3]dioxol-5-yl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-phenylpropyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(cyclopropylmethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((cyclobutyl(phenyl)methyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(1,3-dihydroxypropan-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione;

6-(((S)-1-(4-fluorophenyl)propan-2-yl)amino)-3-((S)-1,1,1-trifluoropropan-2-yl)pyrimidine-2,4(1H,3H)-dione;

-   (S)-6-((1-(3-hydroxyphenyl)ethyl)amino)-3-i    sopropylpyrimidine-2,4(1H,3H)-dione;-   6-((1-(2-hydroxyphenyl)ethyl)amino)-3-i    sopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-phenylethyl)amino)-3-(1-(trifluoromethyl)cyclopropyl)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(3,5-difluorophenyl)-6-((1-(4-fluorophenyl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(2-chlorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-isopropyl-6-((1-(4-methoxyphenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((cyclopropyl(phenyl)methyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-ethyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(cyclopropylmethyl)-6-((1-(3-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-(cyclopropylmethyl)-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-(cyclopropylmethyl)pyrimidine-2,4(1H,3H)-dione;-   (S)-5-chloro-6-((1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)ethypamino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-fluorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3-chlorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione;-   (S)-3-propyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-3-cyclobutyl-6-((1-(4-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(2-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(3,4-difluorophenyl)ethyl)amino)-3-ethylpyrimidine-2,4(1H,3H)-dione;-   3-(((S)-sec-butyl)-6-(((S)-1-(4-fluorophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione;-   (S)-6-((1-(4-fluorophenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione;    and-   (S)-3-(6-fluoropyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione,    or a pharmaceutically acceptable salt of any of the above.

In some embodiments, the compound is selected from

or a pharmaceutically acceptable salt thereof.

The compounds or pharmaceutically acceptable salts described herein (I)can be prepared via any suitable method. Compounds can be prepared, forexample, by the route outlined in FIG. 1 . As shown in FIG. 1A, apyrimidine trione v can be synthesized via condensation of a urea iiiwith a malonate iv. The urea iii can be prepared via reaction of anamine i with an appropriate cyanate ii. The pyrimidine trione v isderivatized with a suitable leaving group (Lg) to provide intermediatevi. The leaving group can be, but is not limited to, a halogen such as achloride or iodide. A halogenated intermediate vi can be prepared frompyrimidine triones by methods such as those described by Brown (TheChemistry of Heterocyclic Compounds, The Pyrimidines, John Wiley & Sons,2009). Intermediates vi can be converted to compounds of formula I viareaction with amines vii. Certain chiral amines can be prepared from aketone or aldehyde ix as shown in FIG. 1B; a sulfinyl imine xii derivedfrom the ketone or aldehyde can be reacted with a Gringard reagent xiiito provide a chiral amine vii. One of skill in the art will appreciatethat the compounds described herein can be prepared via other methods,such as those described by LaRock (Comprehensive OrganicTransformations: A Guide to Functional Group Preparations, Wiley, 1999).

IV. Compositions

Also provided is a pharmaceutical composition containing a compound orpharmaceutically acceptable salt described herein and a pharmaceuticallyacceptable excipient. The compositions may be useful for treatinghypertrophic cardiomyopathy in humans and other subjects.

The pharmaceutical compositions for the administration of the compoundsor pharmaceutically acceptable salts described herein may convenientlybe presented in unit dosage form and may be prepared by any of themethods known in the art of pharmacy and drug delivery. All methodsinclude the step of bringing the active ingredient into association witha carrier containing one or more accessory ingredients. In general, thepharmaceutical compositions are prepared by uniformly and intimatelybringing the active ingredient into association with a liquid carrier ora finely divided solid carrier or both, and then, if necessary, shapingthe product into the desired formulation. In the pharmaceuticalcomposition, the active agent is generally included in an amountsufficient to produce the desired effect upon myocardial contractility(i.e. to decrease the often supranormal systolic contractility in HCM)and to improve left ventricular relaxation in diastole. Such improvedrelaxation can alleviate symptoms in hypertrophic cardiomyopathy andother etiologies of diastolic dysfunction. It can also ameliorate theeffects of diastolic dysfunction causing impairment of coronary bloodflow, improving the latter as an adjunctive agent in angina pectoris andischemic heart disease. It can also confer benefits on salutary leftventricular remodeling in HCM and other causes of left ventricularhypertrophy due to chronic volume or pressure overload from, e.g.,valvular heart disease or systemic hypertension.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups, elixirs, solutions, buccalpatch, oral gel, chewing gum, chewable tablets, effervescent powder andeffervescent tablets. Compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents, antioxidants and preserving agents inorder to provide pharmaceutically elegant and palatable preparations.Tablets contain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as cellulose, silicon dioxide, aluminum oxide, calciumcarbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, corn starch, or alginic acid; binding agents, forexample PVP, cellulose, PEG, starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated, enterically or otherwise,by known techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate may be employed. They may also becoated to form osmotic therapeutic tablets for controlled release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.Additionally, emulsions can be prepared with a non-water miscibleingredient such as oils and stabilized with surfactants such asmono-diglycerides, PEG esters and the like.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxy-ethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions described herein may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. Oral solutions can be prepared in combination with, for example,cyclodextrin, PEG and surfactants.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds or pharmaceutically acceptable salts described herein mayalso be administered in the form of suppositories for rectaladministration of the drug. These compositions can be prepared by mixingthe drug with a suitable non-irritating excipient which is solid atordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials includecocoa butter and polyethylene glycols. Additionally, the compounds orpharmaceutically acceptable salts can be administered via oculardelivery by means of solutions or ointments. Still further, transdermaldelivery of the subject compounds or pharmaceutically acceptable saltscan be accomplished by means of iontophoretic patches and the like. Fortopical use, creams, ointments, jellies, solutions or suspensions, etc.,containing the compounds or pharmaceutically acceptable salts describedherein are employed. As used herein, topical application is also meantto include the use of mouth washes and gargles.

The compounds or pharmaceutically acceptable salts described herein mayalso be coupled to a carrier that is a suitable polymer for targetabledrug carriers. Such polymers can include polyvinylpyrrolidone, pyrancopolymer, polyhydroxy-propyl-methacrylamide-phenol,polyhydroxyethyl-aspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds orpharmaceutically acceptable salts described herein may be coupled to acarrier that is a biodegradable polymer useful in achieving controlledrelease of a drug, such as polylactic acid, polyglycolic acid,copolymers of polylactic and polyglycolic acid, polyepsiloncaprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross linked or amphipathicblock copolymers of hydrogels. Polymers and semipermeable polymermatrices may be formed into shaped articles, such as valves, stents,tubing, prostheses and the like.

V. Methods of Treating Cardiac Disorders

The mutations that lead to HCM cause significant perturbations in myosinmechanics. These mutations exert their effects via distinct mechanismsdepending on their locations in the myosin gene. The well-studied HCMmutations, R403Q and R453C, are located in different sections of themotor domain and cause distinct mechanistic perturbations that lead tothe common outcome of increased force production. Without wishing to bebound by any particular theory, it is believed that the compounds orpharmaceutically acceptable salts described herein can bind directly tothe mutant sarcomeric proteins and correct for their aberrant function,either in cis (by affecting the same specific function) or in trans (byaltering a complementary function). As such, they can providetherapeutic benefit for HCM patients by counteracting thehypercontractile and/or impaired relaxation associated with thisdisease.

Also provided is a method of treating hypertrophic cardiomyopathy (HCM)or a cardiac disorder having one or more pathophysiological featuresassociated with HCM. The method includes administering to a subject inneed thereof an effective amount of a compound or pharmaceuticallyacceptable salt described herein.

The compounds of the invention or their pharmaceutically acceptablesalts can alter the natural history of HCM and other diseases ratherthan merely palliating symptoms. The mechanisms conferring clinicalbenefit to HCM patients can extend to patients with other forms of heartdisease sharing similar pathophysiology, with or without demonstrablegenetic influence. For example, an effective treatment for HCM, byimproving ventricular relaxation during diastole, can also be effectivein a broader population characterized by diastolic dysfunction. Thecompounds of the invention or their pharmaceutically acceptable saltscan specifically target the root causes of the conditions or act uponother downstream pathways. Accordingly, the compounds of the inventionor their pharmaceutically acceptable salts can also confer benefit topatients suffering from diastolic heart failure with preserved ejectionfraction, ischemic heart disease, angina pectoris, or restrictivecardiomyopathy. Compounds of the invention or their pharmaceuticallyacceptable salts can also promote salutary ventricular remodeling ofleft ventricular hypertrophy due to volume or pressure overload; e.g.,chronic mitral regurgitation, chronic aortic stenosis, or chronicsystemic hypertension; in conjunction with therapies aimed at correctingor alleviating the primary cause of volume or pressure overload (valverepair/replacement, effective antihypertensive therapy). By reducingleft ventricular filling pressures the compounds could reduce the riskof pulmonary edema and respiratory failure. Reducing or eliminatingfunctional mitral regurgitation and/or lowering left atrial pressuresmay reduce the risk of paroxysmal or permanent atrial fibrillation, andwith it reduce the attendant risk of arterial thromboemboliccomplications including but not limited to cerebral arterial embolicstroke. Reducing or eliminating either dynamic and/or static leftventricular outflow obstruction may reduce the likelihood of requiringseptal reduction therapy, either surgical or percutaneous, with theirattendant risks of short and long term complications. The compounds ortheir pharmaceutically acceptable salts may reduce the severity of thechronic ischemic state associated with HCM and thereby reduce the riskof Sudden Cardiac Death (SCD) or its equivalent in patients withimplantable cardioverter-defibrillators (frequent and/or repeated ICDdischarges) and/or the need for potentially toxic antiarrhythmicmedications. The compounds or their pharmaceutically acceptable saltscould be valuable in reducing or eliminating the need for concomitantmedications with their attendant potential toxicities, drug-druginteractions, and/or side effects. The compounds or theirpharmaceutically acceptable salts may reduce interstitial myocardialfibrosis and/or slow the progression, arrest, or reverse leftventricular hypertrophy.

Depending on the disease to be treated and the subject's condition, thecompounds or pharmaceutically acceptable salts described herein may beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, ICV, intracisternal injection or infusion, subcutaneousinjection, or implant), by implantation (e.g., as when the compound orpharmaceutically acceptable salt is coupled to a stent device), byinhalation spray, nasal, vaginal, rectal, sublingual, or topical routesof administration and may be formulated, alone or together, in suitabledosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants and vehicles appropriatefor each route of administration.

In the treatment or prevention of conditions which require improvedventricular relaxation during diastole, an appropriate dosage level willgenerally be about 0.001 to 100 mg per kg patient body weight per daywhich can be administered in single or multiple doses. In someembodiments, the dosage level will be about 0.01 to about 25 mg/kg perday; in some embodiments, about 0.05 to about 10 mg/kg per day. Asuitable dosage level may be about 0.01 to 25 mg/kg per day, about 0.05to 10 mg/kg per day, or about 0.1 to 5 mg/kg per day. Within this rangethe dosage may be 0.005 to 0.05, 0.05 to 0.5 or 0.5 to 5.0 mg/kg perday. In some embodiments, for oral administration, the compositions areprovided in the form of tablets containing 1.0 to 1000 milligrams of theactive ingredient, particularly 1.0, 5.0, 10.0, 15.0, 20.0, 25.0, 50.0,75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0, 600.0, 750.0,800.0, 900.0, and 1000.0 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the patient to be treated. Thecompounds or pharmaceutically acceptable salts may be administered on aregimen of 1 to 4 times per day, in some embodiments, once or twice perday.

It will be understood, however, that the specific dose level andfrequency of dosage for any particular patient may be varied and willdepend upon a variety of factors including the activity of the specificcompound or pharmaceutically acceptable salt employed, the metabolicstability and length of action of that compound or pharmaceuticallyacceptable salt, the age, body weight, hereditary characteristics,general health, sex and diet of the subject, as well as the mode andtime of administration, rate of excretion, drug combination, and theseverity of the particular condition for the subject undergoing therapy.

Compounds and compositions provided herein may be used in combinationwith other drugs that are used in the treatment, prevention, suppressionor amelioration of the diseases or conditions for which compounds andcompositions provided herein are useful. Such other drugs may beadministered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound or compositionprovided herein. When a compound or composition provided herein is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound orcomposition provided herein is preferred. Accordingly, thepharmaceutical compositions provided herein include those that alsocontain one or more other active ingredients or therapeutic agents, inaddition to a compound or composition provided herein. Suitableadditional active agents include, for example: therapies that retard theprogression of heart failure by down-regulating neurohormonalstimulation of the heart and attempt to prevent cardiac remodeling(e.g., ACE inhibitors, angiotensin receptor blockers (ARBs), β-blockers,aldosterone receptor antagonists, or neural endopeptidase inhibitors);therapies that improve cardiac function by stimulating cardiaccontractility (e.g., positive inotropic agents, such as the β-adrenergicagonist dobutamine or the phosphodiesterase inhibitor milrinone); andtherapies that reduce cardiac preload (e.g., diuretics, such asfurosemide) or afterload (vasodilators of any class, including but notlimited to calcium channel blockers, phosphodiesterase inhibitors,endothelin receptor antagonists, renin inhibitors, or smooth musclemyosin modulators). The weight ratio of the compound provided herein tothe second active ingredient may be varied and will depend upon theeffective dose of each ingredient. Generally, an effective dose of eachwill be used.

VI. Examples

Abbreviations:

-   aq: aqueous-   BBr₃: boron tribromide-   CH₂Cl₂: dichloromethane-   CH₃CN: acetonitrile-   CH₃OH: methanol-   DIAD: diisopropyl azodicarboxylate-   DIEA: diisopropyl ethylamine-   DMF: dimethyl formamide-   DMSO: dimethyl sulfoxide-   equiv.: equivalents-   Et₃N: triethylamine-   Et₂O: diethyl ether-   EtOH: ethanol-   FeSO₄: ferrous sulfate-   h: hour(s)-   HCl: hydrogen chloride-   H₂O: water-   K₂CO₃: potassium carbonate-   KHSO₄: potassium bisulfate-   KNCO: potassium isocyanate-   LiBr: lithium bromide-   MgSO₄: magnesium sulfate-   mL: milliliter-   MW: microwave (reaction done in microwave reactor)-   NaCl: sodium chloride-   NaH: sodium hydride-   NaHCO₃: sodium bicarbonate-   NaOEt: sodium ethoxide-   NaOH: sodium hydroxide-   NaOMe: sodium methoxide-   Na₂SO₄: sodium sulfate-   NH₄Cl: ammonium chloride-   NMP: n-methyl pyrrolidinone-   pH: —log [W⁺]-   POCl₃: phosphoryl trichloride-   PPTS: pyridinium p-toluenesulfonate-   RP-HPLC: reversed phase high pressure liquid chromatography-   RT: room temperature-   SEMCl: 2-(trimethylsilyl)ethoxymethyl chloride-   TEBAC: triethylbenzylammonium chloride-   TFA: trifluoroacetic acid-   THF: tetrahydrofuran-   TLC: thin layer chromatography

Example 1. Preparation of (S)-3-Isopropyl-6-((1-phenyl ethyl)amino)pyrimidine-2, 4(1H,3H)-dione.

Compound 1.1. Isopropylurea. To a stirred solution of isopropylamine(15.3 g, 0.258 mol, 1.0 equiv) in CH₂Cl₂ (200 mL) under argon at 0° C.was added dropwise trimethylsilyl isocyanate (30 g, 0.26 mol, 1.0equiv). The resulting mixture was allowed to reach ambient temperatureand stirred overnight. After cooling to 0° C., CH₃OH (100 mL) was addeddropwise. The resulting solution was stirred for 2 hours (h) at roomtemperature and then concentrated under reduced pressure. The cruderesidue was recrystallized from CH₃OH:Et₂O (1:20) to yield 15.4 g (58%)the title compound as a white solid. LC/MS: m/z (ES+) 103 (M+H)⁺.

Compound 1.2. 1-Isopropyl barbituric acid. To a stirred solution of 1.1(14.4 g, 0.14 mol, 1.00 equiv) in CH₃OH (500 mL) were added dimethylmalonate (19.55 g, 0.148 mol, 1.05 equiv) and sodium methoxide (18.9 g,0.35 mol, 2.50 equiv). The resulting mixture was stirred overnight at65° C. After cooling to ambient temperature and then to 0° C., the pHwas carefully adjusted to 3 using aqueous concentrated HCl. Theresulting mixture was concentrated under reduced pressure. The residuewas taken up in EtOH (200 mL) and filtered. The filtrate wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography using CH₂Cl₂/CH₃OH (20:1) as eluent toyield 16.8 g (50%) of the title compound as a white solid. . LC/MS: m/z(ES+) 171 (M+H)⁺.¹ ¹-NMR (300 MHz, d₆-DMSO): δ 11.19 (s, 1H), 4.83 (m,1H), 3.58 (s, 2H), 1.32 (d, J=6.0 Hz, 6H).

Compound 1.3. 6-chloro-3-isopropylpyrimidine-2,4(1H, 3H)-dione. To a100-mL round-bottom flask containing compound 1.2 (11.4 g, 66.99 mmol,1.00 equiv) under argon were added triethylbenzylammonium chloride (21.3g, 93.51 mmol, 1.40 equiv) and POCl₃ (30 mL). The resulting mixture wasstirred overnight at 50° C. After cooling to room temperature, themixture was concentrated under reduced pressure. The residue wasdissolved in CH₂Cl₂ (150 mL) followed by slow addition of H₂O (100 mL).The phases were separated and the organic layer was washed with H₂O (100mL), dried with anhydrous Na₂SO₄, and concentrated under reducedpressure. The crude residue was purified by silica gel columnchromatography using EtOAc/petroleum ether (1:1) as eluent to yield 5.12g (40%) of the title compound as a light yellow solid. ¹H-NMR (300 MHz,d₆-DMSO): δ 12.22 (s, 1H), 5.88 (s, 1H), 4.95 (m, 1H), 1.34 (d, J=6.0Hz, 6H).

Compound 1. (S)-3-Isopropyl-6-((1-phenylethyl) amino) pyrimidine-2,4(111,311)-dione. To a solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 1.0 g, 5.31 mmol) in 1,4-dioxane (20 mL) was added(S)-α-methylbenzylamine (Sigma-Aldrich, 1.43 g, 11.7 mmol, 2.2 equiv).The reaction mixture was stirred at 80° C. for 24 h. After cooling toambient temperature, the mixture was concentrated under reducedpressure. The residual was taken up in EtOAc (70 mL) and washed withaqueous 1N HCl (2×50 mL) and brine (40 mL). The organic layer was driedwith anhydrous Na₂SO₄ and then concentrated under reduced pressure tohalf the original volume to yield a precipitate. Hexane (20 mL) wasadded and the mixture was stirred at room temperature. The resultingsolid was collected by filtration, washed with hexane (20 mL), and driedto yield 1.0 g (69%) of the title compound as a white solid. LC/MS: m/z(ES+) 274 (M+H)⁺.¹H-NMIR (400 MHz, d₆-DMSO): δ 9.77 (s, 1H), 7.32 (m,4H), 7.24 (m, 1H), 6.50 (d, J=6.8 Hz, 1H), 4.87 (m, 1H), 4.52 (m, 1H),4.31 (d, J=6.8 Hz, 1H), 1.37 (m, 3H), 1.24 (m, 6H). ¹H NMR (400 MHz,CD₃OD) δ ppm 7.39-7.20 (m, 5H), 5.01 (m, 1H), 4.48 (m, 1H), 1.49 (d,J=6.7 Hz, 3H), 1.36 (m, 6H).

Example 2. Preparation of(S)-5-Fluoro-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione(2).

To a solution of 1 (80 mg, 0.293 mmol) in acetic acid (2.0 mL) was addedselectfluor (104 mg, 0.293 mmol, 1.0 equiv.). The mixture was stirred atroom temperature for 2 h. It was then concentrated under reducedpressure. The residue was purified by silica gel column chromatography,eluted with 0-50% EtOAc in hexanes to give 6 mg (7%) of the titlecompound as a white solid. LC/MS: m/z (ES+) 292 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD): δ ppm 7.36-7.24 (m, 5H), 5.04-4.97 (m, 1H), 4.94-4.88 (m, 1H),1.54 (d, J=8.0 Hz, 3H), 1.39 (m, 6H).

Example 3. Preparation of(S)-5-Bromo-3-isopropyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione(3).

To a solution of 1 (55 mg, 0.201 mmol) in acetic acid (1.0 mL) was addedN-bromosuccinamide (35 mg, 0.196 mmol). The mixture was stirred at roomtemperature for 1 hour. It was then concentrated under reduced pressure.The residue was purified by a silica gel column, eluted with 0-40% EtOAcin hexanes to give 52 mg (74%) of the title compound as a white solid.LC/MS: m/z (ES+) 352, 354 (M+H, bromine pattern)⁺. ¹H-NMR (400 MHz,CDCl₃) δ ppm 8.96 (br s, 1H), 7.43-7.28 (m, 5H), 5.28 (d, J=7.4 Hz, 1H),5.14 (m, 1H), 4.87 (m, 1H), 1.62 (d, J=6.7 Hz, 3H), 1.45-1.39 (m, 6H).

Example 4. Preparation of(S)-6-((1-(3-Chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 4.1. 5-Fluoro-1-isopropylpyrimidine-2,4,6(1H,3H,5H)-trione). Toa 100 mL round bottom flask containing a solution of 1.1 (1.31 g, 0.013mol, 1.00 equiv) in CH₃OH (15 mL) were added diethyl fluoromalonate(2.41 g, 0.014 mol, 1.05 equiv) and sodium methoxide (1.74 g, 0.032 mol,2.50 equiv). The reaction flask was equipped with a reflux condenser andwas stirred for 4 h in an oil bath heated at 85° C. The reaction wascooled to 0° C. and was quenched with careful addition of concentratedHCl, adjusting to pH=2 with the addition of excess concentrated HCl. Thereaction mixture was concentrated under reduced pressure and theresulting residue was dried for 18 h under high vacuum to provide 2.65 gof the title compound (98%). ¹H-NMR (400 MHz, CDCl₃): δ ppm 5.53 (d,J=24.0 Hz, 1H), 4.91 (m, 2H), 1.46 (m, 6H).

Compound 4.2. 6-Chloro-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione.To a 100-mL round-bottom flask equiped with a reflux condensorcontaining 4.1 (2.65 g, 0.014 mmol, 1.00 equiv) were addedtriethylbenzylammonium chloride (4.50 g, 0.019 mmol, 1.40 equiv) andPOCl₃ (25 mL). The reaction mixture was stirred for 4 h at 50° C. andthen was cooled to room temperature. The mixture was concentrated underreduced pressure and the resulting residue was dissolved in CH₂Cl₂ (50mL). Water (50 mL) was added slowly and the layers were separated. Theorganic layer was washed a second time with H₂O (100 mL), dried withanhydrous MgSO₄, and concentrated under reduced pressure. The resultingresidue was purified by flash chromatography (silica gel, 30% EtOAc inhexanes) to yield 2.67 g (93%) of the title compound as a white solid.¹H-NMR (400 MHz, CDCl₃): δ ppm 5.19-5.05 (m, 2H), 1.48 (d, J=7.04 Hz,

Compound 4.(S)-6-((1-(3-Chlorophenyl)ethyl)amino)-5-fluoro-3-isopropylpyrimidine-2,4(1H,3H)-dione.To a solution of 4.2 (150 mg, 0.70 mmol, 1 equiv) in DMF (2 mL)contained in a heavy wall pressure vessel were added(S)-3-chloro-α-methylbenzylamine (150 mg, 0.70 mmol, 1.0 equiv) andproton sponge (190 mg, 0.90 mol, 1.25 equiv). The pressure vessel wassealed and the reaction mixture was heated to 95° C. for 3 h behind ablast shield. The reaction mixture was cooled to room temperature andconcentrated under reduced pressure. The resulting residue was purifiedby preparative RP-HPLC utilizing a Shimadzu, Prominence LC-20AP systemequipped with a Phenomenex Gemini-NX C₁₈ column (eluting with 10-90%CH₃CN/H₂O in 30 min., 20 mL/min (both containing 0.1% TFA)). Thefractions containing pure compound were combined and lyophilized toprovide 30 mg (13%) of the title compound as a white solid. LC/MS: m/z(ES+) 326 (M+H)⁺. ¹H-NMR (400 MHz, CDCl₃) δ ppm 9.47 (br s, 1H),7.35-7.27 (m, 3H), 7.22-7.16 (m, 1H), 5.12 (m, 1H), 4.89 (m, 1H), 4.69(d, J=5.9 Hz, 1H), 1.59 (d, J=6.7 Hz, 3H), 1.43 (m, 6H).

Example 5. Preparation of(S)-6-((1-(3,5-Difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 5.1.((R,E)-N-(3,5-difluorobenzylidene)-2-methylpropane-2-sulfinamide. To asolution of 3,5-difluorobenzaldehyde (1.00 g, 7.04 mmol, 1.00 equiv) inCH₂Cl₂ (20 mL) were added pyridinium p-toluenesulfonate (0.089 g, 0.35mmol, 0.05 equiv), (R)-(+)-2-methylpropane-2-sulfinamide (0.852 g, 7.03mmol, 1.00 equiv), and MgSO₄ (4.2 g, 35.00 mmol, 5.00 equiv). Theresulting mixture was stirred overnight at room temperature. Thereaction mixture was filtered and concentrated under reduced pressure.The resulting residue was purified by flash chromatography (silica gel,20% EtOAc in petroleum ether) to provide 500 mg (29%) of the titlecompound as a yellow oil.

Compound 5.2.(R)-N-((S)-1-(3,5-difluorophenyl)ethyl)-2-methylpropane-2-sulfinamide.Methylmagnesium bromide (5.17 mL, 3M, 2.00 equiv) was added dropwise toa solution of 5.1 (1.9 g, 7.75 mmol, 1.00 equiv) in CH₂Cl₂ (50 mL) underargon at −48° C. The reaction mixture was warmed to room temperature andstirred overnight. The reaction was carefully quenched with a saturatedaqueous NH₄Cl solution (20 mL). The layers were separated and theaqueous layer was further extracted with CH₂Cl₂ (3×50 mL). The combinedorganic layers were dried over anhydrous MgSO₄ and concentrated underreduced pressure to provide 1.3 g (64%) of the title compound as ayellow oil. ¹H NMR (300 MHz, CDCl₃): δ ppm 6.92-6.81 (m, 2H), 6.75-6.65(m, 1H), 4.65-4.55, (m, 1H), 3.46-3.42 (m, 1H), 1.53-1.44 (m, 3H),1.26-1.22 (m, 9H).

Compound 5.3. (S)-1-(3,5-Difluorophenyl)ethan-1-amine hydrochloride. Toa solution of 5.2 (1.3 g, 4.97 mmol, 1.00 equiv) in CH₃OH (10 mL) wasadded 4N HCl in 1,4-dioxane (2.67 mL, 2.00 equiv). The reaction mixturewas stirred for 0.5 h at room temperature and then was concentratedunder reduced pressure. The resulting residue was dissolved in CH₃OH (3mL) and Et₂O (300 mL) was added. The resulting precipitate was isolatedby filtration to provide 0.80 g (83%) of the title compound. ¹H NMR (300MHz, D₂O): δ ppm 6.98-6.83 (m, 3H), 4.45-4.38 (m, 1H), 1.51-1.48 (d,J=6.9 Hz, 3H).

Compound 5.(S)-6-((1-(3,5-Difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.Compound 5.3 (50 mg, 0.32 mmol, 1.00 equiv) was dissolved in 1N NaOH (10mL), and the resulting mixture was stirred at 25° C. After 1 h, themixture was extracted with EtOAc (5×10 mL). The combined organic layerswere dried with anhydrous Na₂SO₄, filtered, and concentrated underreduced pressure. The resulting residue and compound 1.3 (35.6 mg, 0.19mmol, 0.60 equiv) were combined. The mixture was stirred at 100° C. for18 h, then was cooled to room temperature and concentrated under reducedpressure. The resulting residue was purified by preparative RP-HPLC toprovide 28 mg (29%) of the title compound as an off white solid. LC/MS:m/z (ES+) 310 (M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.83 (s, 1H),7.06-7.12 (m, 3H), 6.54 (d, J=6.6 Hz, 1H), 4.91-4.82 (m, 1H), 4.54-4.46(m, 1H), 4.30 (m, 1H), 1.34 (d, J=6.6 Hz, 3H), 1.22 (d, J=6.9 Hz, 6H).

Example 6. Preparation of(S)-6-((Cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 6.1. (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide. Thetitle compound was prepared in the same manner as 5.1 exceptbenzaldehyde (5.0 g, 47.12 mmol, 1.00 equiv) was used in place of3,5-difluorobenzaldehyde to provide 2.8 g (28%) of the title compound.¹H NMR (300 MHz, d₆-DMSO): δ ppm 8.62 (s, 1H), 7.89-7.87 (m, 2H),7.55-7.49 (m, 3H), 1.31 (s, 9H).

Compound 6.2.(S)-N-((S)-Cyclopropyl(phenyl)methyl)-2-methylpropane-2-sulfinamide. Thetitle compound was prepared using a protocol similar to that used forthe preparation of 5.2 except 6.1 (1.0 g, 4.78 mmol, 1.00 equiv) andcyclopropylmagnesium bromide (9.6 mL, 1M, 2.00 equiv) were used in placeof 5.1 and methylmagnesium bromide to provide 0.5 g (35%) of the titlecompound as a yellow oil. ¹H NMR (300 MHz, DMSO-d₆): δ ppm 7.36-7.23 (m,5H), 3.67-3.51 (m, 2H), 1.31 (m, 10H), 0.85-0.15 (m, 4H).

Compound 6.3. (S)-Cyclopropyl(phenyl)methanamine hydrochloride. Thetitle compound was prepared using a protocol similar to that used forthe preparation of 5.3 except 6.2 (500 mg, 1.69 mmol, 1.00 equiv) wasused in place of 5.2 to provide 220 mg (88%) of the title compound as ayellow oil. ¹H NMR (300 MHz, d₆-DMSO): δ ppm 7.37-7.31 (m, 5H), 3.53 (d,J=10.0 Hz, 1H), 1.37-1.25 (m, 1H), 0.75-0.55 (m, 1H), 0.53-0.31 (m, 2H),0.25-0.15 (m, 1H).

Compound 6.(S)-6-((Cyclopropyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.The title compound was prepared using a procedure similar to that usedfor the preparation of 5 except 6.3 (200 mg, 1.36 mmol, 1.00 equiv) wasused instead of 5.3 and 1,4-dioxane was utilized as a solvent. Afterconcentration under reduced pressure, purificaiton utilizing a chiralHPLC (Phenomenex Lux 5μ Cellulose-4, 2.12*25, 5 μm column) with anisocratic mixture of EtOH: Hexane (1: 4) as eluent provided 22 mg (5%)of the title compound as a white solid. LC/MS: m/z (ES+) 300 (M+H)⁺.¹H-NMR (300 MHz, DMSO-d₆) δ ppm 9.82 (s, 1H), 7.39-7.25 (m, 5H),7.25-7.32 (m, 1H), 6.72 (m, 1H), 4.90 (m, 1H), 4.22 (s, 1H), 3.78 (m,1H), 1.27 (m, 6H), 1.57 (m, 1H), 0.60 (m, 1H), 0.56-0.32 (m, 2H).

Example 7. Preparation of(S)-6-((cyclopropyl(3-methoxyphenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

A solution of 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.3, 50mg, 0.265 mmol), (S)-cyclopropyl-(3-methoxyphenyl)methylamine(Sigma-Aldrich, 104 mg, 0.587 mmol), and proton sponge (85 mg, 0.397mmol) in NMP (0.5 mL) was stirred at 130° C. for 2 h. After cooling toroom temperature, the mixture was purified by preparative RP-HPLC(Shimadzu, Prominence LC-20AP system equipped with a PhenomenexGemini-NX C₁₈ column), eluting with 20-90% CH₃CN in H₂O (both containing0.1% TFA). The fractions containing pure compound were combined andlyophilized to give 10 mg (11%) of the title compound as a white solid.LC/MS: m/z (ES+) 330 (M+H)⁺. ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.26 (t,J=7.8 Hz, H), 6.92-6.79 (m, 3H), 5.00 (m, 1H), 3.79 (s, 3H), 3.74 (d,J=8.6 Hz, 1H), 1.36 (d, J=7.0 Hz, 6H), 1.23-1.13 (m, 1H), 0.68-0.60 (m,1H), 0.58-0.50 (m, 1H), 0.50-0.42 (m, 1H), 0.41-0.34 (m, 1H).

Example 8. Preparation of(S)-6-((Cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 8.1.(S,E)-N-(cyclobutylmethylene)-2-methylpropane-2-sulfinamide. To asolution of cyclobutanecarbaldehyde (1.0 g, 11.89 mmol, 1.00 equiv) inCH₂Cl₂ (10 mL) were added pyridinium p-toluenesulfonate (0.143 g, 0.57mmol, 0.05 equiv), (S)-(−)-2-methylpropane-2-sulfinamide (1.22 g, 10.07mmol, 0.85 equiv), and magnesium sulfate (7.14 g, 59.32 mmol, 5.00equiv). The resulting mixture was stirred overnight at room temperature.The reaction mixture was filtered and concentrated under reducedpressure. The resulting residue was purified by flash chromatography(silica gel, 30% EtOAc in petroleum ether) to provide 2.0 g (90%) of thetitle compound as a white solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.08 (d,J=10.8 Hz, 1H), 3.36-3.32 (m, 1H), 2.25-2.16 (m, 4H), 2.03-1.90 (m, 2H),1.15 (s, 9H).

Compound 8.2.(S)-N-((S)-cyclobutyhphenyl)methyl)-2-methylpropane-2-sulfinamide.Phenylmagnesium bromide (3M in Et₂O, 15.3 mL, 2.00 equiv) was addeddropwise to a solution of 8.1 (4.3 g, 22.96 mmol, 1.00 equiv) in THF (40mL). The reaction mixture was heated for 3 h at 65° C. It was thencooled to room temperature and carefully quenched with a saturatedaqueous NH₄Cl solution (30 mL). The resulting mixture was extracted withEtOAc (3×30 mL), and the combined organic layers were dried withanhydrous Na₂SO₄ and concentrated under reduced pressure to provide 5.8g (95%) of the title compound as a white solid. ¹H-NMR (300 MHz, CDCl₃)δ 7.30-7.21 (m, 5H), 4.23 (d, J=9.6 Hz, 1H), 2.73-2.68 (m, 1H),1.95-1.60 (m, 6H), 1.14 (s, 9H).

Compound 8.3. (S)-Cyclobutyhphenyl)methanamine hydrochloride. The titlecompound was prepared using a procedure similar to that used for thepreparation of 5.3 except 8.2 (5.8 g, 0.022 mol, 1.00 equiv) was used inplace of 5.2 to provide 3.20 g (91%) of the title compound as a whitesolid. ¹H NMR (300 MHz, D₂O): δ ppm 7.36-7.28 (m, 5H), 4.18 (m, 1H),2.87-2.73 (m, 1H), 2.11-2.01 (m, 1H), 1.90-1.69 (m, 5H).

Compound 8.(S)-6-((Cyclobutyl(phenyl)methyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.Compound 8.3 (0.200 g, 1.24 mmol, 1.00 equiv) was dissolved in 1N NaOH(10 mL), and was stirred for 1 h at 25° C. The reaction mixture wasextracted with EtOAc (5×10 mL). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated under reduced pressure.The resulting residue was dissolved in NMP and combined with 1.3 andproton sponge and heated as described for the preparation of 7. Thetitle compound (35 mg, 9%) was isolated as a white solid. LC/MS: m/z(ES+) 314 (M+H)⁺. ¹H NMR (300 MHz, CD₃OD): δ ppm 7.38-7.26 (m, 5H),5.08-4.97 (m, 1H), 4.25 (d, J=6.9 Hz, 1H), 2.68-2.58 (m, 1H), 2.19-2.13(m, 1H), 1.98-1.83 (m, 5H), 1.36 (d, J=6.9 Hz, 6H).

Example 9. Preparation of(S)-6-((1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione.

Compound 9.1. 1-(tetrahydro-2H-pyran-4-yl)urea. A mixture oftetrahydro-2H-pyran-4-amine (5.0 g, 49.4 mmol, 1.0 equiv.) and potassiumisocyanate (4.0 g, 49.5 mmol, 1.0 equiv.) was refluxed in H₂O (50 mL)overnight. The reaction was cooled to room temperature and excess NaClwas added to help saturate the aqueous layer. The precipitate wasisolated by filtration to provide the desired product (1.28 g, 8.88mmol). The aqueous layer was washed with EtOAc (3×15 mL) and then wasconcentrated and azeotroped with toluene (3×100 mL). The resulting solidwas suspended in 1:4 CH₃OH:EtOAc (100 mL) and filtered a total of fourtimes. The combined organics were concentrated under reduced pressureand combined with the isolated precipitate to provide 5.01 g (70%) ofthe title compound. LC/MS: m/z (ES+) 145 (M+H)⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ 6.14 (d, J=7.5 Hz, 1H), 5.47 (s, 2H), 3.85 (dt, J=11.6, 3.6Hz, 2H), 3.65-3.52 (m, 1H), 3.38 (td, J=11.4, 2.2 Hz, 2H), 1.80-1.72 (m,2H), 1.42-1.27 (m, 2H).

Compound 9.2.1-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. Compound9.1 (2.8 g, 19.4 mmol) was dissolved in EtOH (30 mL), and diethylmalonate (2.45 mL, 21.4 mmol, 1.1 equiv.), and NaOEt (7.55 mL, 23.3mmol, 1.2 equiv.) were added. The reaction was stirred at 85° C.overnight, and then was cooled to room temperature. The reaction mixturewas diluted with H₂O (5 mL), and excess KHSO₄ was added to saturate theaqueous layer. The reaction mixture was extracted with EtOAc (3×15 mL).The combined organic layers were dried with anhydrous MgSO₄, filteredand concentrated under reduced pressure. The resulting residue waspurified by flash chromatography (silica gel, 0-25% CH₃OH in CH₂Cl₂) toprovide 1.57 g of a mixture containing the title compound which was usedwithout further purification. LC/MS: m/z (ES−) 211 (M−H)⁻.

Compound 9.3.6-chloro-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione. To asolution of 9.2 (1.57 g, 7.4 mmol, 1 equiv.) in CH₃CN (15 mL) was addedPOCl₃ (0.551 mL, 5.9 mmol, 0.8 equiv.). The reaction mixture was stirredat 80° C. overnight. An additional aliquot of POCl₃ (0.4 equiv.) wasadded and the reaction mixture was stirred at 80° C. for 3h. Additionalaliquots of POCl₃ (0.4 equiv.) were added after 3 h and 5 h of stirringat 80° C. The reaction mixture was then stirred at 90° C. for 1h. Thereaction was cooled to room temperature, concentrated, swirled with Et₂O(15 mL) and decanted. The resulting residue was rinsed with Et₂O (15 mL)and decanted until the Et₂O decanted clear. The resulting residue wascarefully suspended in CH₃OH (10 mL), and filtered. The filtrate wasconcentrated to obtain a mixture of starting material and the titlecompound (˜85% pure, 1.6 g). LC/MS: m/z (ES−) 229 (M−H)⁻.

Compound 9.(S)-6-((1-phenylethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione.A mixture of 9.3 (0.15 g, 0.65 mmol, 1 equiv.) and(S)-(−)-α-methylbenzylamine (470 mg, 3.88 mmol, 6.0 equiv.) was stirredovernight at 90° C. The reaction mixture was cooled to room temperatureand the resulting residue was purified by preparative RP-HPLC (0-40%CH₃CN in H₂O in 30 min.), followed by a second purification on apreparatory TLC plate (2000 um) (7% CH₃OH in CH₂Cl₂) to provide 23 mg(11%) of the title compound. LC/MS: m/z (ES+) 316 (M+H)⁺. ¹H NMR (400MHz, DMSO-d₆): δ ppm 10.23 (s, 1H), 7.40-7.32 (m, 4H), 7.31-7.17 (m,1H), 6.93 (s, 1H), 4.84-4.71 (m, 1H), 4.56-4.43 (m, 1H), 4.35 (s, 1H),3.93-3.78 (m, 2H), 3.28 (t, J=12.1 Hz, 2H), 2.63-2.39 (m, 2H), 1.40 (d,J=6.7 Hz, 3H), 1.35-1.16 (m, 2H).

Example 10. Preparation of(S)-6-((1-(3-methoxyphenyl)ethyl)amino)-3-(tetrahydro-2H-pyran-4-yl)pyrimidine-2,4(1H,3H)-dione(10).

To a solution of 9.3 (0.58 g, 0.25 mmol) in a mixture of 2-propanol andH₂O (4:1, 1 mL) was added (S)-1-(3-methoxyphenyl)-ethylamine (0.113 g,0.75 mmol, 3.0 equiv.). The reaction mixture was heated to 120° C. for 2h. After cooling, the reaction mixture was concentrated under reducedpressure, dissolved in CH₃OH and filtered. The filtrate was purified bypreparative RP-HPLC (20-100% CH₃CN in H₂O in 40 min. at 25 mL/min.) toprovide 18 mg (21%) of the title compound as an off-white solid. LC/MS:m/z (ES+) 346 (M+H)⁺. ¹H NMR (400 MHz, acetone-d₆) δ 8.90 (s, 1H), 7.15(dd, J=8.3, 8.1 Hz, 1H), 6.88 (s, 1H), 6.86 (d, J=8.3 Hz, 1H), 6.68 (d,J=8.1 Hz, 1H), 6.15 (s, 1H), 4.74 (m, 1H), 4.48 (m, 1H), 4.35 (s, 1H),3.82 (m, 2H), 3.68 (s, 3H), 3.2 (m, 2H), 2.55 (m, 2H) 1.44 (d, J=6.6 Hz,3H) , 1.15 (m, 2H).

Example 11. Preparation of6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione.

Compound 11.1.6-chloro-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione. To a mixture of 6-chloro-uracil (3.0 g, 20.47 mmol, 1 equiv.)and LiBr (1.78 g, 20.5 mmol, 1.0 equiv.) in NMP (70 mL) at 0° C. wasadded NaH (60% dispersion in mineral oil, 0.82 g, 20.5 mmol, 1.0equiv.). The reaction mixture was stirred at 0° C. for 10 min, and2-(trimethylsilyl)ethoxymethyl chloride (3.75g, 22.5 mmol, 1.1 equiv.)was slowly added via an addition funnel. The reaction mixture wasstirred overnight at room temperature and then diluted with EtOAc (150mL). The mixture was washed with a saturated aqueous NH₄Cl solution (50mL), saturated aqueous NaHCO₃ (50 mL), and brine (50 mL). The organiclayer was dried with anhydrous Na₂SO₄ and concentrated under reducedpressure to provide 3.2 g (57%) of the title compound as a white solid.LC/MS: m/z (ES+) 299 (M+Na)⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm 9.00-8.80(br-s, 1H), 5.95 (s, 1H), 5.45 (s, 2H)), 3.63 (t, J=7.0 Hz, 2H), 1.48(t, J=7.0 Hz, 2H), 0.01 (s, 9H).

Compound 11.2.6-chloro-3-(tetrahydrofuran-3-yl)-1-(2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione.To a solution of 11.1 (277 mg, 1.0 mmol, 1 equiv.),3-hydroxytetrahydrofuran (106 mg, 1.2 mmol, 1.2 equiv.), andtriphenylphosphine (320 mg, 1.2 mmol, 1.2 equiv.) in THF (7.5 mL) at 0°C., was added diisopropyl azodicarboxylate (0.240 g, 1.2 mmol, 1.2equiv.) dropwise. The reaction mixture was stirred at room temperaturefor 30 minutes. The reaction mixture was concentrated under reducedpressure and the resulting residue was purified by preparative RP-HPLC(20-100% CH₃CN in H₂O with 0.1% formic acid buffer in 40 min. at 25mL/min.) to provide 102 mg (29%) of the title compound. LC/MS: m/z (ES+)347 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) δ 5.92 (s, 1H), 5.58 (m, 1H),5.41(s, 2H), 4.20 (m, 1H), 4.00-3.85 (m, 3H), 3.65 (t, J=7.0 Hz, 2H),2.35-2.20 (m, 1H), 2.20-2.08 (m, 1H), 0.95 (t, 2H), 0.01 (s, 9H); ¹³CNMR (CDCl₃) δ 160.7, 150.7, 145.6, 102.0, 74.8, 68.7, 67.9, 67.5, 51.9,28.7, 18.0, 0.0.

Compound 11.3.6-chloro-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione. Compound11.2 (0.50 g, 1.4 mmol, 1.0 equiv.) was dissolved in trifluoroaceticacid (1 mL). The reaction mixture was stirred at room temperature for 30minutes and then was concentrated under reduced pressure. The resultingresidue was purified by preparative RP-HPLC (10% CH₃CN in H₂O in 40 min.at 25 mL/min.) to provide 300 mg (96%) of the title compound as a whitesolid. LC/MS: m/z (ES+) 217 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆): δ ppm5.90 (s, 1H), 5.35 (m, 1H), 4.00 (m, 1H), 3.85-3.68 (m, 3H), 2.20 (m,1H), 2.01 (m, 1H).

Compound 11.6-(((S)-1-phenylethyl)amino)-3-(tetrahydrofuran-3-yl)pyrimidine-2,4(1H,3H)-dione.The title compound was prepared using a procedure similar to that usedfor the preparation of 9 except 11.3 (22 mg, 0.10 mmol, 1.00 equiv) wasused in place of 9.3 to provide 15 mg (50%) of the title compound as awhite solid. LC/MS: m/z (ES+) 302 (M+H)⁺. ¹H NMR (400 MHz, CDCl₃): δ ppm10.50 (1H), 7.50-7.20 (m, 5H), 5.90 (m, 1H), 5.60 (m, 1H), 4.78 (m, 1H),4.45 (s, 1H), 4.20 (m, 1H), 4.05-3.90 (m, 2H), 3.90-3.80 (m, 1H),2.45-2.10 (m, 2H), 1.55 (d, J=6.7 Hz, 3H).

Example 12. Preparation of(S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-(1-phenylethylamino)pyrimidine-2,4(1H,3H)-dione.

Compound 12.1. tert-Butyl 4-(3-benzoylureido)piperidine-1-carboxylate.To a solution of benzoylisocyanate (4.8 g, 32.6 mmol) in CH₂Cl₂ (180 mL)at 0° C. was added 4-amino-1-N-boc-piperidine (6.0 g, 30 mmol). Thereaction mixture was stirred at room temperature for 4 h andconcentrated. The residue was treated with Et₂O (100 mL). Theprecipitate was filtered and washed with Et₂O to yield 5.70 g (55%) ofthe title compound as a white solid. LC/MS: m/z (ES+) 337 (M+H)⁺.

Compound 12.2. tert-Butyl 4-ureidopiperidine-1-carboxylate. To a mixtureof 12.1 (5.60 g, 16.1 mmol) in CH₃OH (70 mL) and H₂O (70 mL) was addedsodium hydroxide (11.6 g, 290 mmol) portionwise. The reaction mixturewas stirred at room temperature overnight and then refluxed for 1 h. Themixture was cooled to room temperature and concentrated under reducedpressure to remove CH₃OH. The precipitate was filtered, washed with H₂O,and dried to yield 3.2 g (82%) of the title compound as a white solid.LC/MS: m/z (ES+) 266 (M+Na)⁺.

Compound 12.3. tert-Butyl4-(2,4,6-trioxo-tetrahydropyrimidin-1(2H)-yl)piperidine-1-carboxylate.To a mixture of 12.2 (3.63 g, 14.9 mmol), diethylmalonate (2.6 mL, 16.5mmol, 1.1 equiv.) and anhydrous ethanol (60 mL) was added NaOEt (21% inEtOH, 6.6 mL, 17.7 mmol, 1.2 equiv.). The mixture was refluxed for 14 hand concentrated. The residue was taken up in H₂O (15 mL) and washedwith EtOAc (2×30 mL). The aqueous layer was separated and adjusted topH=5 with concentrated. HCl. The precipitate was filtered, washed withH₂O and dried to give 3.70 g (80%) of the title compound as an off-whitesolid. LC/MS: m/z (ES+) 334 (M+Na)⁺.

Compound 12.4. 6-chloro-3-(piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione.To a mixture of 12.3 (2.55 g, 8.19 mmol) and POCl₃ (10 mL, 100.65 mmol)was added H₂O (0.41 mL, 22.78 mmol) dropwise. The mixture was stirred at120° C. for 30 min and then concentrated. The residue was carefullytaken up in ice water (20 g). To the mixture was added K₂CO₃ (˜8.0 g)portionwise until the pH was ˜7. The precipitate was filtered, washedwith H₂O (20 mL) and EtOAc (50 mL). The resulting material was dried toyield 1.45 g (77%) of the title compound as an off-white solid. LC/MS:m/z (ES+) 230 (M+H)⁺.

Compound 12.5.6-chloro-3-(1-(methylsulfonyl)piperidin-4-yl)pyrimidine-2,4(1H,3H)-dione.To a mixture of 12.4 (380 mg, 1.65 mmol, 1.0 equiv.) and CH₂Cl₂ (8 mL)was added Et₃N (0.70 mL, 4.95 mmol, 3 equiv.) and methanesulfonylchloride (0.23 mL, 2.5 mmol, 1.5 equiv.). The mixture was stirred atroom temperature for 2 h and then quenched with H₂O (3 mL) to yieldprecipitate. The precipitate was filtered and washed with CH₂Cl₂ (3×3mL). The filtrate was concentrated to ˜1.5 mL. Filtration of a secondprecipitate was followed by washing with H₂O (2×1 mL) and CH₂Cl₂ (3×2mL). The precipitates were combined to afford 320 mg (63%) of the titlecompound as an off-white solid. LC/MS: m/z (ES+) 308 (M+H)⁺.

Compound 12.(S)-3-(1-(methylsulfonyl)piperidin-4-yl)-6-(1-phenylethylamino)pyrimidine-2,4(1H,3H)-dione.A mixture of 12.5 (20 mg, 0.065 mmol) and (S)-α-methylbenzylamine (180mg, 1.5 mmol, 23 equiv.) was stirred at 125° C. for 1 h. The mixture wasconcentrated under reduced pressure, dissolved in CH₃OH and filtered.The filtrate was purified using preparative RP-HPLC eluting with lineargradient 20% to 100% CH₃CN in H₂O (0.1% formic acid buffer) over 40 minto give 16 mg (63%) of the title compound as an off-white solid. LC/MS:m/z (ES+) 393 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.40 (br s, 1H),7.35-7.25 (m, 4H), 7.15 (m, 1H), 6.55 (s, 1H), 4.58 (m, 1H), 4.42 (m,1H), 4.30 (s, 1H), 3.52 (m, 2H), 2.79 (s, 3H), 2.70-2.62 (m, 2H),2.50-2.48 (m, 2H), 1.48-1.38 (m, 2H), 1.32 (d, J=6.8 Hz, 3H).

Example 13. Preparation of (S)-methyl4-(2,6-dioxo-4-(1-phenylethylamino)-2,3-dihydropyrimidin-1(6H)-yl)piperidine-1-carboxylate.

Compound 13.1. Methyl4-(4-chloro-2,6-dioxo-2,3-dihydropyrimidin-1(6H)-yl)piperidine-1-carboxylate.To a mixture of 12.4 (115 mg, 0.5 mmol, 1.0 equiv.) and CH₂Cl₂ (2 mL)was added Et₃N (0.14 mL, 1.5 mmol, 3.0 equiv.), followed by methylchloroformate (95 mg, 1.0 mmol, 2.0 equiv.). The mixture was stirred atroom temperature for 1 h, diluted with CH₂Cl₂ (8 mL), washed with asaturated aqueous NaHCO₃ solution (1 mL), H₂O (1 mL), brine (1 mL),dried with anhydrous Na₂SO₄ and concentrated to yield 105 mg (73%) of anoff-white solid. LC/MS: m/z (ES+) 288 (M+H)⁺.

Compound 13. (S)-methyl4-(2,6-dioxo-4-(1-phenylethylamino)-2,3-dihydropyrimidin-1(6H)-yl)piperidine-1-carboxylate.A mixture of 13.1 (58 mg, 0.20 mmol) and (S)-α-methylbenzylamine (240mg, 1.5 mmol) was stirred at 120° C. for 0.5 h. The title compound wasprepared using a procedure similar to that used for the preparation of 9to provide 40 mg (63%) of the title compound as an off-white solid.LC/MS: m/z (ES+) 373 (M+H)⁺. ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.85 (s,1H), 7.29-7.15 (m, 5H), 5.75 (br s, 1), 4.80 (m, 1H), 4.60 (s, 1H), 4.35(m, 1H), 4.20-4.00 (m, 2H), 3.58 (s, 3H), 2.80-2.70 (m, 2H), 2.46 (m,2H), 1.50 (m, 2H), 1.38 (d, J=6.7 Hz, 3H).

Example 14. Preparation of3-(R)-sec-butyl-6-((S)-1-(3-methoxyphenyl)ethylamino)pyrimidine-2,4(1H,3H)-dione.

Compound 14.1. (R)-1-sec-butylurea. Benzoyl isocyanate (5.36 g, 36.5mmol, 1.05 equiv.) was dissolved in CH₂Cl₂ (20 mL) and cooled to 0° C.in an ice bath. (R)-butan-2-amine (2.54 g, 34.7 mmol, 1 equiv.) inCH₂Cl₂ (10 mL) was carefully added while stirring. The mixture wasallowed to stir for 3 h at room temperature. After the reaction wasdeemed complete, the mixture was concentrated. The residue was suspendedin Et₂O (20 mL) and filtered. The solid was taken up in a 1:1 mixture ofCH₃OH and H₂O (200 mL) followed by the addition of NaOH (6.9 g, 174mmol, 5 equiv.). The reaction was stirred overnight at room temperature.The CH₃OH was evaporated from the solution and the resulting precipitate(1.66 g, 39%) was collected. LC/MS: m/z (ES+) 117 (M+H)⁺.

Compound 14.2. (R)-1-sec-butylpyrimidine-2,4,6(1H,3H,5H)-trione.Compound 14.1 (1.66 g, 14.3 mmol, 1.0 equiv.) was dissolved in EtOH (10mL) , and diethyl malonate (1.8 mL, 15.7 mmol, 1.1 equiv.), and NaOEt(5.6 mL, 17.1 mmol, 1.2 equiv.) were added. The reaction was stirred at80° C. for 2 h and then cooled to room temperature. Water (20 mL) wasadded and then EtOH was removed by evaporation. KHSO₄ (excess) was addedto saturate the aqueous layer which was then extracted with EtOAc. Thecombined organics were dried with anhydrous MgSO₄ and concentrated toyield 1.6 g (61%) of the title compound as a crude residue which wasused without further purification. LC/MS: m/z (ES−) 183 (M−H)⁻.

Compound 14.3. (R)-3-sec-butyl-6-chloropyrimidine-2,4(1H,3H)-dione. Amixture of 14.2 (1.6 g, 8.7 mmol, 1 equiv.) and POCl₃ (648 7.0 mmol,0.8equiv.) in CH₃CN (10 mL) was stirred at 90° C. for 2 h. AdditionalPOCl₃ (0.8 equiv.) was added and stirred at 90° C. for 3 h. The reactionwas cooled to room temperature, carefully quenched with CH₃OH (10 mL),stirred for 30 minutes and purified with normal phase HPLC 0-25%CH₃OH/CH₂Cl₂ followed by a CH₃OH flush. The product and startingmaterial co-eluted. The mixture was concentrated, the residue was takenup in CH₃CN (10 mL) and POCl₃ (648 uL) was added. The reaction wasstirred at 90° C. for 3 h and then cooled to room temperature. Thereaction was carefully quenched with CH₃OH (10 mL) and stirred for 30minutes. The reaction mixture was purified by normal phase HPLC withprevious condition, concentrated and dried under vacuum to yield 450 mg(32%) of the title compound as an off-white solid. LC/MS: m/z (ES−) 201(M−H)⁻.

Compound 14.3-(R)-sec-butyl-6-(S)-1-(3-methoxyphenyl)ethylamino)pyrimidine-2,4(1H,3H)-dione. A mixture 14.3 (150 mg, 0.74 mmol, 1.0 equiv.) in neat(S)-1-(3-methoxyphenyl)ethanamine (400 uL) was stirred overnight at 90°C. The reaction was purified using preparative RP-HPLC on an Agilentsystem with a gradient of 0-40% CH₃CN in H₂O over 45 min to yield 13 mg(6%) of the title compound as an off-white solid. LC/MS: m/z (ES+) 318(M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.79 (s, 1H), 7.28 (t, J=8.1Hz, 1H), 6.94-6.88 (m, 2H), 6.84 (dd, J=8.2, 1.7 Hz, 1H), 6.51 (d, J=6.4Hz, 1H), 4.72-4.59 (m, 1H), 4.47 (m, 1H), 4.35 (s, 1H), 3.76 (s, 3H),1.98-1.84 (m, 1H), 1.61 (m, 1H), 1.39 (d, J=6.7 Hz, 3H), 1.25 (d, J=6.9Hz, 3H), 0.70 (t, J=7.4 Hz, 3H).

Example 15. Preparation of(S)-6-(1-phenylethylamino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione.

Compound 15.1. 1-(pyridin-3-yl)urea. Benzoyl isocyanate (3.28 g, 22.3mmol, 1.05 equiv.) was taken up in CH₂Cl₂ (30 mL) and cooled to −10° C.Pyridin-3-amine (2 g, 21.2 mmol, 1 equiv.) was added in portions whilestirring. The mixture was allowed to stir for 3 h at room temperature.After the reaction was deemed complete, it was concentrated and thentaken up in a 1:1 mixture of CH₃OH and H₂O (100 mL) followed by theaddition of NaOH (4.25 g, 106.3 mmol, 5 equiv.). The reaction wasallowed to stir overnight at room temperature, concentrated to dryness,and then azeotroped three times with toluene. A mixture of 10% CH₃OH inEtOAc (100 mL) was added to the solid and stirred for 10 minutesfollowed by filtration. The solid was suspended and filtered twoadditional times. The combined filtrates were filtered once more toremove any solids that passed through the filter and concentrated. Theresidue was triturated with EtOAc (5 mL) and dried under vacuum to yield3.5 g of crude material (off-white solid) that was utilized withoutfurther purification. LC/MS: m/z (ES+) 138 (M+H)⁺.

Compound 15.2. 1-(pyridin-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione.Compound 15.1 (3.0 g, 21.8 mmol, 1.0 equiv.) was taken up in EtOH (20mL), followed by the addition of diethyl malonate (2.75 mL, 24.1 mmol,1.1 equiv.), and NaOEt (8.5 mL, 26.3 mmol, 1.2 equiv.). The reaction wasstirred at 85° C. overnight and then cooled to room temperature. Water(100 mL) was added slowly followed by careful addition of sodiumbicarbonate (8 g). The resulting mixture was washed three times withEtOAc. The aqueous layer was concentrated to 50 mL and CH₃OH (150 mL)was added. The precipitate was removed by filtration and the filtratewas concentrated. The resulting residue was purified flashchromatography (silica gel, 0-25% CH₃OH/CH₂Cl₂) to yield 1.70 g (38%) ofthe title compound as a light yellowish solid. LC/MS: m/z (ES+) 206(M+H)⁺.

Compound 15.3. 6-chloro-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione. Amixture of 15.2 (700 mg, 3.41 mmol, 1.0 equiv.) and POCl₃ (255 2.7 mmol,0.8 equiv.) in CH₃CN (10 mL) was stirred at 90° C. for 2 h. AdditionalPOCl₃ (0.8 equiv) was added and stirring was continued at 90° C. for 2h. Additional POCl₃ (1.6 equiv.) was added followed by the carefuladdition of H₂O (150 ul 2.5 equiv.) The reaction was stirred overnightat 90° C. After cooling to room temperature, the mixture was filteredand the solid was carefully washed with CH₃OH (1 mL). Ethyl acetate (20mL) was added to the filtrate and the resulting precipitate wascollected by filtration and dried under vacuum to yield 230 mg (30%) ofthe title compound as a light yellowish solid. LC/MS: m/z (ES+) 224(M+H)⁺.

Compound 15.(S)-6-(1-phenylethylamino)-3-(pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione.A mixture of 15.3 (100 mg, 0.45 mmol, 1 equiv.) in neat(S)-(−)-α-methylbenzylamine (500 uL) was stirred overnight at 100° C.After cooling, the reaction was purified using preparative RP-HPLC on anAgilent system with a gradient of 0-40% CH₃CN in H₂O over 45 min.,followed by a second purification on a preparatory TLC plate (2000 um)with 7% CH₃OH/CH₂Cl₂ to yield 39.5 mg (28%) of the title compound.LC/MS: m/z (ES+) 309 (M+H)⁺. ¹H-NMIR (400 MHz, DMSO-d₆): δ ppm 11.15 (s,1H), 8.49 (dd, J=4.8, 1.4 Hz, 1H), 8.34 (d, J=2.4 Hz, 1H), 7.65-7.58 (m,1H), 7.44 (dd, J=8.1, 4.8 Hz, 1H), 7.37 (m, 5H), 7.26 (m, 1H), 4.61-4.53(m, 1H), 4.48 (s, 1H), 1.39 (d, J=6.8 Hz, 3H).

Example 16. Preparation of(S)-3-(Isoxazol-3-yl)-6-(1-phenylethylamino)pyrimidine-2,4(1H,3H)-dione(16).

The title compound was prepared using procedures similar to those usedfor the preparation of compound 15 except isoxazol-3-amine was used inplace of pyridin-3-amine. LC/MS: m/z (ES+) 299 (M+H)⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ ppm 8.96 (s, 1H), 7.38 (d, J=3.9 Hz, 4H), 7.28 (dd, J=8.4,4.3 Hz, 2H), 7.10 (s, 1H), 6.63 (s, 1H), 4.74-4.52 (m, 1H), 4.48 (s,1H), 1.44 (d, J=6.6 Hz, 3H).

Example 17. Preparation of(S)-6-((1-(3-(1H-pyrazol-1-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione(17).

The title compound was prepared by Ullman coupling (P.E. Fanta. “TheUllmann Synthesis of Biaryls”. Synthesis, 1974, 9-21) of 35 with1H-pyrazole in the presence of copper iodide, cesium carbonate, andtrans-N,N′-dimethylcyclohexane-1,2-diamine. LC/MS: m/z (ES+) 340 (M+H)⁺.¹H-NMR (400 MHz, CD₃OD): δ ppm 8.26 (s, 1H), 7.70 (m, 2H), 7.66 (m, 1H),7.51 (m, 1H), 7.34 (m, 1H), 6.55 (s, 1H), 5.05 (m, 1H), 4.62 (m, 1H),1.58 (d, J=6.8 Hz, 3H), 1.37 (m, 6H).

Example 18. Preparation of Additional Pyrimidine Dione Compounds.

The compounds in Table 1 were prepared according to the examples asdescribed above.

TABLE 1 Compounds and Analytical Data Compound No. Structure Ref.Example Observed Mass and/or ¹H NMR

19R 1 274 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.42-7.22 (m, 5H),5.06-4.94 (m, 1H), 4.49 (m, 1H), 1.49 (d, J = 7.0 Hz, 3H), 1.36 (m, 6H).

20R 1 304 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.39 (br s, 1H),7.29-7.23 (m, 1H), 6.88-6.79 (m, 3H), 5.31 (br s, 1H), 5.09 (m, 1H),4.78 (br s, 1H), 4.48-4.34 (m, 1H), 3.80 (s, 3H), 1.51 (d, J = 7.0 Hz,3H), 1.44-1.38 (m, 6H).

21 1 304 (M + H)⁺ 1H-NMR (400 MHz, CD₃OD): δ ppm 7.26 (t, J = 7.9 Hz,1H), 6.92-6.85 (m, 2H), 6.85-6.80 (m, 1H), 5.01 (m, 1H), 4.45 (d, J =7.0 Hz, 1H), 3.79 (s, 3H), 1.48 (d, J = 7.0 Hz, 3H), 1.37 (d, J = 7.0Hz, 6H).

22 1 304 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.29-7.17 (m, 1 H),7.00 (d, J = 7.4 Hz, 1 H), 6.93 (m, 1 H), 5.05-4.97 (m, 1 H), 4.83 (s, 1H), 4.80-4.74 (m, 1 H), 3.89 (s, 3 H), 1.45 (d, J = 6.7 Hz, 3 H), 1.38-1.34 (m, 6 H).

24 1 288 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.76 (br s, 1H),7.41-7.13 (m, 5H), 6.50 (d, J = 7.0 Hz, 1H), 4.88 (m, 1H), 4.31 (d, J =2.4 Hz, 1H), 4.24 (m, 1H), 1.83-1.58 (m, 2H), 1.35-1.10 (m, 6H), 0.83(m, 3H).

25 1 288 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 7.46-7.29 (m, 4H),7.27-7.21 (m, 1H), 6.27 (d, J = 9.0 Hz, 1H), 6.08 (br s, 1H), 5.13 (m,1H), 4.98 (m, 1H), 1.78 (s, 3H), 1.46 (m, 3H), 1.29 (m, 6H).

26 1 292 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.45 (br s, 1H),7.30-7.23 (m, 2H), 7.16-7.01 (m, 2H), 5.13 (dt, J = 13.8, 7.0 Hz, 1H),4.99 (br s, 1H), 4.74-4.63 (m, 2H), 1.55 (d, J = 6.7 Hz, 3H), 1.43 (m,6H).

27 1 292 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.28 (br s, 1H),7.36-7.28 (m, 1H), 7.06 (d, J = 7.8 Hz, 1H), 7.02-6.93 (m, 2H),5.17-5.04 (m, 1H), 4.95-4.82 (m, 1H), 4.75-4.70 (m, 1H), 4.50-4.40 (m,1H), 1.53 (d, J = 7.0 Hz, 3H), 1.46-1.37 (m, 6H).

28 1 308 (M + H)⁺ ¹H NMR (400 MHz, CD₃OD): δ ppm 7.39-7.31 (m, 2H),7.29-7.23 (m, 2H), 5.01 (m, 1H), 4.50 (q, J = 6.7 Hz, 1H), 1.48 (d, J =7.0 Hz, 3H), 1.37 (d, J = 7.0 Hz, 6H).

29 ---- 1 304 (M + H)⁺ ¹H NMR (400 MHz, CD₃OD): δ ppm 7.38-7.26 (m, 5H),5.04-4.97 (m, 1H), 4.56 (dd, J = 7.4, 3.9 Hz, 1H), 3.67-3.63 (m, 1H),3.56-3.51 (m, 1H), 3.37 (s, 3H), 1.36 (m, 6H).

30 1 292 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.34 (m, 2H), 7.08 (m,2H), 5.07-4.95 (m, 1H), 4.50 (q, J = 6.8 Hz, 1H), 1.48 (d, J = 6.7 Hz,3H), 1.37 (m, 6H).

31 4 & 5 306 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.70 (br s, 1H),7.39-7.22 (m, 5H), 5.19- 5.07 (m, 1H), 4.85 (br s, 1H), 4.73-4.61 (m,1H), 1.88 (dq, J = 14.3, 7.0 Hz, 2H), 1.45 (m, 6H), 0.96 (t, J = 7.4 Hz,3H).

32 4 & 5 310 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.89 (br s, 1 H),7.40-7.29 (m, 1 H), 7.13- 6.95 (m, 3 H), 5.12 (m, 1 H), 5.02-4.87 (m, 1H), 4.82-4.69 (m, 1 H), 1.59 (d, J = 6.7 Hz, 3 H), 1.42 (m, 6 H),

33 4 & 5 322 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.50 (br s, 1H),7.30 (dd, J = 9.00, 7.83 Hz, 1H), 6.93-6.90 (m, 3H), 5.19-5.04 (m, 1H),4.88 (m, 1H), 4.75 (m, 1H), 3.79 (s, 3H), 1.59 (d, J = 6.7 Hz, 3H), 1.43(d, J = 7.0 Hz, 6H).

34 6 310 (M + H)⁺ ¹H-NMR (300 MHz, DMSO-d₆): ppm 9.74 (s, 1H), 7.32-7.24(m, 2H), 7.21- 7.13 (m, 1H), 6.60 (s, 1H), 4.95-4.86 (m, 1H), 4.69-4.62(m, 1H), 4.32 (s, 1H), 1.49-1.42 (d, J = 6.6 Hz, 3H), 1.28- 1.26 (d, J =6.9 Hz, 6H).

35 6 352 (M + H)⁺ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.85 (s, 1H), 7.59(s, 1H), 7.48 (m, 1H), 7.38-7.32 (m, 2H), 6.59 (d, J =5.4 Hz, 1H),4.95-4.88 (m, 1H), 4.57-4.50 (m, 1H), 4.36 (s, 1H), 1.41 (d, J = 6.6 Hz,3H), 1.25 (d, J = 6.9 Hz, 6H).

36 1 & 5 274 (M + H)⁺ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.96 (br s, 1H),7.39-7.24 (m, 5H), 6.58 (d, J = 6.6 Hz, 1H), 4.38 (s, 1H), 4.28 (q, J =6.9 Hz, 1H), 3.65 (q, J = 6.6 Hz, 2H), 1.78-1.66 (m, 2H), 0.99 (t, J =6.9 Hz, 3H), 0.86 (t, J = 7.2 Hz, 3H).

37 1 & 5 272 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.83 (s, 1H),7.37 (m, 4H), 7.26 (m, 1H), 6.52 (m, 1H), 4.50 (m, 1H), 4.33 (s, 1H),2.37 (m, 1H), 1.41 (d, J = 6.8 Hz, 3H), 0.85 (m, 2H), 0.60 (m, 2H).

38 15 309 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.92 (s, 1H),8.57-8.42 (m, 1H), 7.85 (ddd, J = 7.8, 7.8, 1.7 Hz, 1H), 7.46- 7.31 (m,5H), 7.32-7.19 (m, 2H), 7.13 (m, 1H), 4.67-4.52 (m, 1H), 4.41 (s, 1H),1.39 (d, J = 6.8 Hz, 3H).

39 15 312 (M+ H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 7.65 (d, J = 2.2 Hz,1H), 7.41-7.35 (m, 5H), 7.32-7.24 (m, 1H), 6.77 (d, J = 5.9 Hz, 1H),6.04 (d, J = 2.1 Hz, 1H), 4.63- 4.55 (m, 1H), 4.42 (s, 1H), 3.79 (s,3H), 1.44 (d, J = 6.7 Hz, 3H).

40 15 299 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d6): δ ppm 11.07 (s, 1H), 8.93(s, 1H), 7.43-7.31 (m, 4H), 7.31-7.04 (m, 2H), 6.59 (s, 1H), 4.62 (m,1H), 4.43 (s, 1H), 1.40 (d, J = 6.7 Hz, 3H).

41 17 341 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.42 (s, 1H), 8.67(s, 1H), 8.13 (s, 1H), 7.71 (s, 1H), 7.61 (m, 1H), 7.51 (m, 1H), 7.37(m, 1H), 5.41 (m, 1H), 5.13 (m, 1H), 4.68 (m, 1H), 4.55 (m, 1H), 1.59(d, J = 6.8 Hz, 3H), 1.44 (m, 6H).

42 17 354 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.85 (s, 1H), 7.52(m, 1H), 7.39 (m, 2H), 7.34 (m, 2H), 6.94 (m, 1H), 6.60 (m, 1H), 4.90(m, 1H), 4.62 (m, 1H), 4.38 (s, 1H), 2.26 (s, 3H), 1.44 (d, J = 9.2 Hz,3H), 1.28 (d, J = 9.2 Hz, 6H).

43 17 359 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.84 (s, 1H), 7.62(s, 1H), 7.42 (m, 2H), 7.12 (d, J = 7.2 Hz, 1H), 6.61 (bs, 1H), 4.91 (m,1H), 4.69-4.43 (m, 3H), 4.34 (s, 1H), 4.09 (m, 2H), 1.42 (d, J = 6.8Hz,3H), 1.28 (m, 6H).

44 15 314 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.28-7.13 (m, 5H),4.52 (m, 1H), 4.39 (m, 2H), 2.22 (m, 2H), 1.69 (m, 2H), 1.54 (m, 1H),1.44-1.40 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H), 1.30-1.20 (m, 2H), 1.20-1.08 (m, 1H).

45 15 308 (M + H)⁺ ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.84 (s, 1H),7.43-7.17 (m, 6H), 7.12 (d, J = 7.3 Hz, 2H), 7.05 (d, J = 6.8 Hz, 2H),5.55 (br s, 1H), 4.68 (s, 1H), 4.25 (m, 1H), 1.18 (d, J = 6.7 Hz, 3H).

46 15 260 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.37-7.30 (m, 4H),7.10-7.06 (m, 1H), 4.55 (s, 1H), 4.51 (q, J = 6.7 Hz, 1H), 3.81 (q, J =7.0 Hz, 2H), 1.50 (d, J = 7.0 Hz, 3H), 1.11 (t, J = 7.0 Hz, 3H).

47 15 246 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.02 (s, 1H),7.38-7.30 (m, 4H), 7.26- 7.22 (m, 1H), 6.56 (s, 1H), 4.52 (q, J = 6.7Hz, 1H), 4.39 (s, 1H), 2.97 (s, 3H) 1.40 (d, J = 6.7 Hz, 3H).

Example 48. Preparation of(S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione.

Compound 48.1. 1-propylurea. To a stirred solution of n-propylamine(2.15 g, 36.5 mmol, 1.00 equiv) in CH₂Cl₂ (35 mL) at 0° C. was addeddropwise trimethylsilyl isocyanate (4.94 g (85% purity), 36.5 mmol, 1.00equiv). The reaction mixture was stirred at room temperature for 72 hand was then cooled to 0° C. The chilled mixture was quenched by thedropwise addition of CH₃OH (10 mL) and was concentrated under reducedpressure. The resulting solid was suspended in Et₂O (30 mL) and wasfiltered. The solid was further washed with Et₂O (30 mL) and dried toafford 2.0 g (38%) of the title compound as a white solid.

Compound 48.2. 1-propylpyrimidine-2,4,6(1H,3H,5H)-trione. To 48.1 (600mg, 5.88 mmol, 1.00 equiv) in CH₃OH (1 mL) was added diethyl malonate(960 mg, 6.0 mmol, 1.02 equiv.) and sodium methoxide (1 mL, 25% NaOCH₃in CH₃OH by weight). The reaction mixture was heated in the microwavereactor at 130° C. for 1 h. The mixture was cooled and the mixture wascarefully adjusted to pH=3 with concentrated HCl. The volatiles wereremoved and H₂O was added (10 mL). Solid precipitated and was filtered.It was further washed with additional H₂O (10 mL) and dried to afford560 mg (56%) of title compopund as a white solid.

Compound 48.3. 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione. Compound48.2 (560 mg, 3.30 mmol) and POCl₃ (2 mL) were added to a heavy wallpressure vessel which was subsequently sealed. The resulting solutionwas heated to 70° C. and stirred for 50 minutes behind a blast shield.The reaction mixture was cooled and concentrated under reduced pressure.To the resulting residue was added CH₂Cl₂ (30 mL) which was then removedunder reduced pressure. The addition and evaporation of CH₂Cl₂ (30 mL)was conducted one additional time and then the resulting residue wasdiluted with CH₂Cl₂ (50 mL). To the organic layer was carefully added asaturated aqueous NaHCO₃ solution (50 mL). The layers were separated andthe organics were further washed with H₂O (30 mL) and brine (30 mL). Theorganic layer was concentrated and purified by flash columnchromatography (silica gel, utilizing 10% EtOAc in CH₂Cl₂) to afford 160mg (26%) of the title compound as a white solid.

Compound 48.(S)-6-((1-phenylethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione. To48.3 (160 mg, 0.85 mmol, 1.0 equiv.) in 1,4-dioxane (1.5 mL) was addedEt₃N (200 μL) and (S)-α-methylbenzylamine (235 mg, 1.94 mmol, 2.3equiv.). The mixture was heated in a microwave reactor at 130° C. for 2h. The mixture was cooled and concentrated. The resulting residue wastreated with an 8:3 mixture of H₂O:CH₃CN which resulted inprecipitation. The solid was filtered and successively washed with H₂O(10 mL) and EtOAc (10 mL). The solid was dried to give 67 mg (29%) ofthe title compound as a white solid. LC/MS: m/z (ES+) 274(M+H)⁺. ¹H-NMR(400 MHz, DMSO-d₆): δ ppm 9.92 (br s, 1H), 7.36-7.22 (m, 5H), 6.54 (d,J=7.0 Hz, 1H), 4.50 (quin, J=6.7 Hz, 1H), 4.35 (s, 1H), 3.54 (dd, J=8.0,6.9 Hz, 2H), 1.42-1.36 (m, 5H), 0.76 (t, J=7.6 Hz, 3H).

Example 49. Preparation of(S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 49.1. 1-(3,5-difluorophenyl)urea. To a stirred solution of3,5-difluoroaniline (4.0 g, 31 mmol, 1.00 equiv) in CH₂Cl₂ (50 mL) underargon at room temperature was added dropwise trimethylsilyl isocyanate(3.56 g, 30.90 mmol, 1.00 equiv). The reaction mixture was stirredovernight and quenched by the dropwise addition of CH₃OH (50 mL). Thereaction mixture was concentrated under reduced pressure and theresulting residue was purified by flash chromatography (silica gel,eluting with CHCl₃/CH₃OH (10:1 to 7:1)) to yield 2.0 g (38%) of thetitle compound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.96(s, 1H), 7.16-7.10 (m, 2H), 6.72-6.66 (m, 1H), 6.07 (br s, 2H).

Compound 49.2. 1-(3,5-difluorophenyl)pyrimidine-2,4,6(1H,3H,5H)-trione.To a stirred solution of 49.1 (1.6 g, 0.0093 mol, 1.1 equiv) in CH₃OH(20 mL) were added diethyl malonate (1.4 g, 0.0087 mol, 1.0 equiv) andsodium methoxide (1.25 g, 0.0231 mol, 2.7 equiv). The resulting mixturewas stirred overnight at 65° C. After cooling to ambient temperature,the pH was carefully adjusted to 5 using aqueous 1N HCl. The resultingsolution was extracted with EtOAc (3×50 mL). The organic layers werecombined and concentrated under reduced pressure. The residue was washedwith CH₃OH (50 mL) and the resulting solid was isolated by filtration togive 700 mg (31%) of the title compound as a white solid. ¹H-NMR (400MHz, DMSO-d₆): δ ppm 11.66 (s, 1H), 7.43-7.35 (m, 1H), 7.11-7.08 (m,2H), 3.77 (s, 2H).

Compound 49.3.6-chloro-3-(3,5-difluorophenyl)pyrimidine-2,4(1H,3H)-dione. To a 25-mLround-bottom flask under argon containing 49.2 (740 mg, 3.08 mmol, 1.00equiv) were added triethylbenzylammonium chloride (840 mg, 1.20 equiv)and POCl₃ (3 mL). The resulting solution was stirred for 4 h at 50° C.The reaction cooled and quenched by the careful addition of water/ice(20 mL). The pH of the solution was adjusted to 5 with 2N sodiumhydroxide. The resulting solution was extracted with EtOAc (2×10 mL) andthe organic layers were combined. The organic layer was washed withbrine (10 mL), dried over anhydrous MgSO₄, filtered, and concentratedunder reduced pressure. This resulted in 500 mg (crude) of the titlecompound as a white solid. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 12.60 (br,1H), 7.38-7.32 (m, 1H), 7.21-7.16 (m, 2H), 6.05 (s, 1H).

Compound 49.(S)-3-(3,5-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To 49.3 (200 mg, 0.77 mmol) was added (S)-α-methylbenzylamine(1.5 mL). The resulting solution was stirred for 2 h at 120° C. Thereaction mixture was diluted with DMF (3 mL) and the crude product (100mg) was purified by preparative RP-HPLC with the following conditions:XBridge Prep C₁₈ OBD Column, Sum, 19*150 mm; mobile phase, H₂O with0.05%TFA and CH₃CN (40.0% CH₃CN to 90.0% in 10 min). This resulted in21.6 mg (8%) of the title compound as a white solid. LC/MS: m/z (ES+)344 (M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.25 (br s, 1H), 7.38-7.35(m, 4H), 7.28-7.21 (m, 2H), 7.03-6.98 (m, 2H), 6.76 (d, J=6.9 Hz, 1H),4.59 (quin, J=6.7 Hz, 1H), 4.50 (d, J=2.0 Hz, 1H), 1.42 (d, J=6.7 Hz,3H).

Example 50. Preparation of(S)-3-isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 50.1.(R,E)-2-methyl-N-(1-(m-tolyl)ethylidene)propane-2-sulfinamide.

To a stirred solution of 1-(3-methylphenyl)ethanone (1.61 g, 12.0 mmol,1.00 equiv.) and (R)-(+)-2-methyl-2-propanesulfinamide (1.94 g, 14 mmol,1.33 equiv.) in THF (50 mL) was added Ti(OEt)₄ (3.19 g, 14 mmol, 1.17equiv.) dropwise. The reaction mixture was stirred for 16 hat 60° C.,cooled to room temperature, and quenched with a saturated aqueous NaHCO₃solution (50 mL). The layers were separated and the aqueous layer wasfurther extracted with EtOAc (2×100 mL). The combined organics wereconcentrated and the resulting residue was purified by flashchromatography (silica gel, eluting with 0-5% CH₃OH in CH₂Cl₂) to afford1.51 g (53%) of the title compound as a white solid. LC/MS: m/z (ES+)238 (M+H)⁺.

Compound 50.2.(R)-2-methyl-N-((S)-1-(m-tolyl)ethyl)propane-2-sulfinamide. To asolution of 50.1 (1.51 g, 6.37 mmol) in THF (30 mL) at −78° C. under anN₂ atmosphere was added L-selectride (dropwise, 10 mL, 1.0 M in THF, 10mmol). The reaction mixture was warmed to 0° C., stirred for 1 h, andcarefully quenched with a saturated aqueous NH₄Cl solution (30 mL). Thelayers were separated and the aqueous layer was further extracted withEtOAc (2×50 mL). The combined organics were concentrated and theresulting residue was purified by flash chromatography (silica gel,eluted with 0-5% CH₃OH in CH₂Cl₂) to afford 0.85 g (56%) of the titlecompound. LC/MS: m/z (ES+) 240 (M+H)⁺.

Compound 50.3. (S)-1-(m-tolyl)ethan-1-amine hydrochloride. To absoluteEtOH (10 mL) was added AcCl (1.5 mL, dropwise). The mixture was stirredfor 10 minutes and then was added to 50.2 (0.85 g, 3.56 mmol) in EtOH (3mL). The reaction mixture was stirred for 2 h at ambient temperature andwas concentrated. The resulting solid was suspended in Et₂O andfiltered. The solid was washed with additional Et₂O and dried to give402 mg (66%) of the title compound as white solid. LC/MS: m/z (ES+) 136(M+H)⁺.

Compound 50.4. (S)-1-(m-tolyl)ethan-1-amine. To a stirred solution of50.3 (205 mg, 1.20 mmol) in CH₂Cl₂ (10 mL) was added MP-carbonate (1.0g, 3.18 mmol/g). The reaction mixture was stirred at room temperaturefor 1 h and was then filtered. The solid beads were washed with anadditional 10 mL CH₂Cl₂ and the combined filtrates were concentrated togive the title compound which was pushed forward without anypurification.

Compound 50.(S)-3-isopropyl-6-((1-(m-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione.To 50.4 (presumed ˜1.2 mmol from prevous reaction, 2.0 equiv.) in a 0.5to 2.0 mL microwave tube was added compound 1.3 (110 mg, 0.59 mmol, 1.0equiv.). The microwave tube was sealed and heated at 120° C. behind ablast shield for 2.5 h. Upon cooling (to ˜60° C.), NMP (2.5 mL) wasadded to the reaction mixture. The mixture was sonicated and heated (to˜60° C.) until the solid completely dissolved. The resulting solutionwas cooled to 40° C. and a 3:1 mixture of H₂O/CH₃CN (5 mL) was added. Asolid precipitated and was collected through filtration. The light beigesolid was subsequently washed with H₂O and dried to give 97 mg (57%) ofthe title compound as a white solid. LC/MS: m/z (ES+) 288 (M+H)⁺. ¹H-NMR(400 MHz, DMSO-d₆): δ ppm 9.73 (br s, 1H), 7.22 (t, J=8.0 Hz, 1H),7.12-7.04 (m, 3H), 6.45 (d, J=8.0 Hz, 1H), 4.90-4.86 (m, 1H), 4.42 (q,J=6.7 Hz, 1H), 4.31 (d, J=2.4 Hz, 1H), 2.29 (s, 3H), 1.36 (d, J=6.7 Hz,3H), 1.27-1.23 (m, 6H).

Example 51. Preparation of(S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 51.1. 2-(4-fluorophenyl)-N-methoxy-N-methylacetamide. To astirred solution of 2-(4-fluorophenyl)acetic acid (15 g, 97.32 mmol,1.00 equiv) in CH₂Cl₂ (300 mL) was added methoxy(methyl)aminehydrochloride (11.1 g, 113.79 mmol, 1.20 equiv), 4-dimethylaminopyridine(12 g, 98.22 mmol, 1.00 equiv), 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28.2 g, 147.10 mmol, 1.50 equiv), and DIEA(37.5 g, 290.14 mmol, 3.00 equiv). The resulting solution was stirred atroom temperature for 16 h and then diluted with EtOAc (150 mL). Theorganics were washed with aqueous 1N HCl (2×150 mL) and brine (2×150mL). It was then dried over anhydrous Na₂SO₄ and concentrated underreduced pressure. The crude residue was purified by flash chromatography(silica gel, eluting with EtOAc/petroleum ether (1:3)). This resulted in18 g (88%) of the title compound as yellow oil. ¹H-NMR (400 MHz, CDCl₃):δ ppm 7.29-7.25 (m, 2H), 7.03-6.99 (m, 2H), 3.75 (s, 2H), 3.65 (s, 3H),3.21 (s, 3H).

Compound 51.2. 2-(4-fluorophenyl)acetaldehyde. To a stirred solution of51.1 (3 g, 15.21 mmol, 1.00 equiv) in THF (60 mL) under argon at −10° C.was added LiAlH₄ (1.15 g, 30.30 mmol, 2.00 equiv) in several batches(CAREFUL . . . EXOTHERMIC REACTION). The resulting solution was stirredfor 1 h at room temperature before being cooled to −10° C. The reactionwas then quenched by the careful addition of a saturated aqueous NH₄Clsolution (50 mL). The resulting solid was filtered and the filtrate wasextracted with EtOAc (3×50 mL). The organic layers were combined, washedwith brine (50 mL), dried with anhydrous Na₂SO₄ and concentrated underreduced pressure to give 2.5 g (crude) of the title compound as a yellowoil.

Compound 51.3. (S)-1-(4-fluorophenyl)propan-2-amine hydrochloride. Thetitle compound was synthesized according to methods described for thepreparation of 5.3, utilizing 51.2 in place of 3,5-difluorobenzaldehyde.LC/MS: m/z (ES+) 154 (M+H)⁺.

Compound 51.4. (S)-1-(4-fluorophenyl)propan-2-amine. To an aqueoussolution of 1N NaOH (5 mL) was added 51.3 (300 mg, 1.59 mmol). Theresulting mixture was stirred for one hour at 25° C. The resultingsolution was extracted with EtOAc (2×10 mL). The organic layer was driedover anhydrous sodium sulfate and concentrated under reduced pressure toyield 160 mg (65%) of the title compound. LC/MS: m/z (ES+) 154 (M+H)⁺.

Compound 51.(S)-6-((1-(4-fluorophenyl)propan-2-yl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.To a stirred solution of 51.4 (160 mg, 1.04 mmol, 2.00 equiv) in NMP(0.5 mL) was added 1.3 (99 mg, 0.52 mmol, 1.00 equiv) and proton sponge(168 mg, 0.78 mmol, 1.50 equiv). The resulting solution was stirred for5 h at 100° C. in an oil bath. The reaction mixture was concentratedunder reduced pressure. The residue (100 mg) was purified by preparativeRP-HPLC to afford 30 mg (19%) of the title compound as gray solid.LC/MS: m/z (ES+) 306 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.81 (brs, 1H), 7.27 (dd, J=8.8, 5.6 Hz, 2H), 7.17-7.12 (m, 2H), 5.89 (d, J=7.6Hz, 1H), 5.00-4.92 (m, 1H), 4.58 (s, 1H), 3.69-3.65 (m, 1H), 2.74 (d,J=6.4 Hz, 2H), 1.31 (d, J=6.8 Hz, 6H), 1.08 (d, J=6.4 Hz, 3H).

Example 52. Preparation of(R)-3-isopropyl-6-((2,2,2-trifluoro-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione(52).

To a 0.2-0.5 mL microwave vial was added 1.3 (85 mg, 0.45 mmol) and(R)-2,2,2-trifluoro-1-phenylethan-1-amine (200 uL, excess). The reactionmixture sealed and heated at 180° C. in a microwave reactor for 40minutes. The reaction mixture was cooled to ambient temperature and thenNMP (1 mL) was added to completely dissolve the solid. Next, a 2:1H₂O/CH₃CN mixture (6 mL) was added which resulted in precipitation. Thesolid was isloated by filtration, washed with H₂O and dried to give 50mg (34%) of the title compound as a white solid. LC/MS: m/z (ES+) 328(M+H)⁺. ¹H-NMR (400 MHz, DMSO-d6): δ ppm 9.79 (br s, 1H), 7.50-7.40 (m,5H), 5.66-5.56 (m, 2H), 4.92-4.87 (m, 2H), 1.28-1.25 (m, 6H).

Example 53. Preparation of3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 53.1. (R)-1-(1-hydroxypropan-2-yl)urea. To a stirred solutionof (R)-(−)-2-amino-1-propanol (0.65 g, 8.68 mmol, 1 equiv.) in CH₂Cl₂(10 mL) under N₂ at 0° C. was added dropwise trimethylsilyl isocyanate(1.00 g, 8.68 mmol, 1.0 equiv.). The reaction mixture was stirredovernight while slowly warming to room temperature. After cooling to 0°C., CH₃OH (10 mL) was added dropwise. The resulting solution was stirredfor 2 h at room temperature and was then concentrated under reducedpressure to provide the title compound (1.02 g, 99%) as a white solid.

Compound 53.2. (R)-1-(1-(benzyloxy)propan-2-yl)urea. To a suspension ofsodium hydride (0.52 g, 13.2 mmol, 1.5 equiv.) in THF (10 mL) at 0° C.was added 53.1 (1.02 g, 8.67 mmol, 1 equiv.). The reaction mixture wasstirred for 20 minutes at 0° C. under N₂ before benzyl bromide (1.03 mL,8.67 mmol, 1 equiv.) was added. The reaction mixture was stirredovernight while slowly warming to room temperature. The reaction mixturewas quenched with H₂O (3 mL) and was extracted into EtOAc (15 mL), driedwith anhydrous Na₂SO₄, filtered, and concentrated. The resulting residuewas purified by flash chromatography (10% CH₃OH in CH₂Cl₂) to provide510 mg (28%) of the title compound. LC/MS: m/z (ES+) 209 (M+H)⁺. ¹H-NMR(400 MHz, CDCl₃): δ ppm 7.42-7.27 (m, 5H), 4.79 (d, J=6.7 Hz, 1H), 4.52(d, J=2.7 Hz, 2H), 3.91 (s, 1H), 3.51 (dd, J=9.4, 3.9 Hz, 1H), 3.40 (dd,J=9.2, 5.3 Hz, 1H), 1.19 (d, J=7.0 Hz, 3H).

Compound 53.3.(R)-1-(1-(benzyloxy)propan-2-yl)pyrimidine-2,4,6(1H,3H,5)-trione. To amicrowave vial containing 53.2 (0.51 g, 2.42 mmol, 1 equiv.) in CH₃OH(10 mL) was added diethyl malonate (2.55 g, 2.55 mmol, 1.05 equiv.)followed by sodium methoxide (25% wt. soln. in CH₃OH, 1.31 g, 6.06 mmol,2.5 equiv.). The vial was capped and the reaction mixture was heated ina microwave reactor for 15 minutes at 150° C. After cooling to roomtemperature, the reaction mixture was quenched with H₂O (2 mL) and thepH was adjusted to 3 with concentrated HCl. The reaction mixture wastransferred to a round bottom flask and was concentrated under reducedpressure. The resulting residue was purified by flash chromatography (5%CH₃OH in CH₂Cl₂) to provide 0.62g (92%) of the title compound as a whitesolid. LC/MS: m/z (ES+) 277 (M+H)⁺. ¹H-NMR (400 MHz, CDCl₃): δ ppm 7.99(s, 1H), 7.38-7.22 (m, 5H), 5.16-5.11 (m, 1H), 4.52 (d, J=12.0 Hz, 1H),4.45 (d, J=12.0 Hz, 1H), 4.02 (t, J=9.8 Hz, 1H), 3.56 (q, J=1.57 Hz,2H), 1.37 (d, J=7.00 Hz, 3H).

Compound 53.4.(R)-3-(1-(benzyloxy)propan-2-yl)-6-chloropyrimidine-2,4(1H,3H)-dione. Toa microwave vial containing 53.3 (0.25 g, 0.91 mmol, 1 equiv.) was addedtriethylbenzylammonium chloride (0.28 g, 1.26 mmol, 1.4 equiv.) andPOCl₃ (1 mL). The vial was capped and the reaction mixture was heated ina microwave reactor for 1 minute at 130° C. The reaction mixture wastransferred to a round bottom flask and was concentrated under reducedpressure. The resulting residue was dissolved in CH₂Cl₂ (5 mL) and water(2 mL) was carefully added. The mixture was stirred for 10 minutes. Thelayers were separated and the organic layer was dried with Na₂SO₄,filtered and concentrated under reduced pressure. The resulting residuewas purified by flash chromatography (silica gel, 5% CH₃OH in CH₂Cl₂) toprovide 150 mg (55%) of the title compound. LC/MS: m/z (ES+) 295 (M+H)⁺.¹H-NMR (400 MHz, CDCl₃): δ ppm 10.27 (s, 1H), 7.36-7.20 (m, 5H),5.32-5.21 (m, 2H), 4.57 (d, J=12.0 Hz, 1H), 4.48 (d, J=12.0 Hz, 1H),4.10 (dd, J=10.0, 9.2 Hz, 1H), 1.40 (d, J=7.0 Hz, 3H).

Compound 53.3-((R)-1-(benzyloxy)propan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.To a microwave vial containing (5)-α-methylbenzylamine (1.5 mL) wasadded 53.4 (0.12 g, 0.42 mmol). The vial was capped and the reactionmixture was heated in a microwave reactor for 10 minutes at 150° C.After cooling, the reaction mixture was filtered through a plug ofsilica gel (10% CH₃OH in CH₂Cl) and the filtrate was concentrated underreduced pressure. The resulting residue was dissolved in CH₂Cl₂ (10 mL)and was washed with 10% HCl (5 mL). The organic layer was dried withanhydrous Na₂SO₄, filtered and concentrated to provide 150 mg (94%) ofthe title compound. LC/MS: m/z (ES+) 380 (M+H)⁺. ¹H-NMR (400 MHz,CDCl₃): δ ppm 9.96 (br s 1H), 7.35-7.24 (m, 10H), 4.70 (br s, 1H),4.53-4.41 (m, 4H), 4.03-3.99 (m, 1H), 3.65-3.61 (m, 1H), 1.49 (d, J=6.7Hz, 3H), 1.37 (d, J=7.0 Hz, 3H).

Example 54. Preparation of3-((R)-1-hydroxypropan-2-yl)-6-(((S)-1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione(54).

To a solution of 53 (0.10 g, 0.26 mmol, 1 equiv.) in EtOH (2 mL) wasadded palladium on carbon (10 wt. % loading (dry basis), matrixactivated carbon, wet support, Degussa type, 0.025 g). The reactionflask was purged with nitrogen and was then fitted with a H_(2(g))balloon. The reaction mixture was evacuated and then filled withH_(2(g)). This pump/purge process was repeated three times and thereaction mixture was stirred for 4 h at room temperature. After purgingwith nitrogen, the reaction mixture was filtered and the filtrate wasconcentrated under reduced pressure. The resulting residue was suspendedin CH₃CN (2 mL) and the precipitate was isolated by filtration. Theprecipitate was dissolved in CH₂Cl₂: CH₃OH (1:1, 2 mL) and was filteredthrough a 0.2 μM PTFE 25 mm filter and was concentrated under reducedpressure to provide 27 mg (35%) of the title compound. LC/MS: m/z (ES+)290 (M+H)⁺. ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.67 (s, 1H), 7.35-7.24 (m,5H), 5.64 (d, J=5.5 Hz, 1H), 5.08-5.04 (m, 1H), 4.66 (s, 1H), 4.42-4.35(m, 1H), 4.24 (s, 1H), 4.04-3.91 (m, 1H), 3.78-3.68 (m, 1H), 1.50 (d,J=6.70 Hz, 3H), 1.35 (d, J=7.00 Hz, 3H).

Example 55. Preparation of(S)-3-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 55.1. (S)-1-(3-(trifluoromethyl)phenyl)ethan-1-aminehydrochloride. The title compound was synthesized according to methodsdescribed for the preparation of 5.3, utilizing3-(trifluoromethyl)benzaldehyde in place of 3,5-difluorobenzaldehyde.

Compound 55.(S)-3-isopropyl-6-((1-(3-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a stirred solution of 55.1 (59.8 mg,0.27 mmol, 1.00 equiv) in DMSO (1.5 mL) under an inert argon atmospherewas added Et₃N (0.2 mL) and 1.3 (50 mg, 0.27 mmol, 1.00 equiv). Theresulting solution was stirred for 6 h at 120° C. in an oil bath. Aftercooling, the mixture was concentrated under reduced pressure and theresulting residue (75 mg) was purified by preparative RP-HPLC to give6.5 mg (7%) of the title compound as a white solid. LC/MS: m/z (ES+) 342(M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 7.78 (s, 1H), 7.74-7.60 (m,3H), 7.20 (br, 1H), 6.02 (br, 1H), 4.96 (dt, J=10.1, 5.1 Hz, 1H),4.67-4.64 (m, 1H), 4.36 (s, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.31-1.28 (m,6H).

Example 56. Preparation of(S)-3-isopropyl-6-((1-(2-cyanophenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione(56).

Intermediate 56.1 was prepared using procedures similar to those for thepreparation of compound 35, utilizing 1.3 and(S)-1-(2-bromophenyl)ethan-1-amine hydrochloride (synthesized from thecorresponding 2-bromobenzaldehyde using methods described for example6.3). To a stirred solution of 56.1 (40 mg, 0.11 mmol, 1.00 equiv,) inDMF (2 mL) was added Zn(CN)₂ (20 mg, 0.17 mmol, 1.50 equiv) andtetrakis(triphenylphosphine) palladium (131 mg, 0.11 mmol, 0.20 equiv).CAUTION. CYANIDE CONTAINING REACTION. The resulting solution was stirredunder an argon atmosphere at 100° C. in an oil bath for 2 h. Uponcooling, the reaction was quenched with a saturated aqueous FeSO₄solution (5 mL). The resulting mixture was diluted with EtOAc (20 mL)and washed with a saturated aqueous FeSO₄ solution (2×20 mL). Theorganic layer was dried with anhydrous Na₂SO₄, filtered, andconcentrated under reduced pressure. The crude product (5 mg) waspurified by chiral preparative HPLC with the following conditions:Column, Phenomenex Lux-2 5u Cellulose-2, 30*150 mm; mobile phase,Hexanes and EtOH (hold 50.0% EtOH in 35 min); resulting in 2.1 mg (6%)of the title compound. LC/MS: m/z (ES+) 299 (M+H)⁺. ¹H-NMR (300 MHz,CD₃CN): δ ppm 8.59 (br s, 1H), 7.73 (d, J=8.4 Hz, 1H), 7.61-7.56 (m,1H), 7.48-7.45 (m, 2H), 5.09-4.94 (m, 3H), 1.46 (d, J=6.6 Hz, 3H),1.34-1.26 (m, 6H).

Example 57. Preparation of(S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 57.1. 3-ethoxy-3-oxo-1-(1-ethoxy)propan-1-iminium chloride. Toa stirred solution of ethyl cyanoacetate (5.0 g, 44 mmol) in anhydrousEt₂O (5 mL) was added absolute EtOH (3 mL). The reaction mixture wascooled to 0° C. and HCl gas was bubbled in for 10 minutes. The reactionmixture was warmed to room temperature and was stirred for 16 h. Thewhite precipitate that formed was filtered and washed with Et₂O (40 mL)and dried to give (6.99 g) the title compound as a white solid. LC/MS:m/z (ES+) 160 (M+H)⁺.

Compound 57.2. Ethyl (S,E/Z)-3-amino-3-((1-phenylethyl)amino)acrylate.To a stirred solution of 57.1 (585 mg, 3.0 mmol) in EtOH (15 mL) wasadded DIEA (0.8 mL), and (S)-α-methylbenzylamine (290 mg, 2.4 mmol). Thereaction was stirred for 16 h and was concentrated. The crude waspurified by flash column chromatography (silica gel, eluting with CH₃OHin CH₂Cl₂ (0 to 10%)) to yield 0.57 g (98%) of the title compound as aclear oil. NMR analysis revealed that the product was a mixture of E/Zisomers. LC/MS: m/z (ES+) 235 (M+H)⁺.

Compound 57.3. Ethyl(S,Z)-3-(3-benzylureido)-3-((1-phenylethyl)amino)acrylate. Two reactionswere set up in parallel and later combined since both resulted information of product (by HPLC). In the first reaction, benzyl isocyanate(150 uL, 1.2 mmol) was added to a stirred solution of 57.2 (143 mg, 0.61mmol) in CH₃CN (1 mL). After 10 min., DIEA (300 uL) was added. Thereaction was stirred for an additional 10 min and was quenched with H₂O(12 mL). Solid precipitated and was removed by filtration. In the secondreaction, benzyl isocyanate (150 uL, 1.2 mmol) was added to a stirredsolution of 57.2 (143 mg, 0.61 mmol) and DIEA (300 uL) in CH₃CN (1 mL).After 10 min, the reaction mixture was quenched with H₂O (10 mL). Theresulting mixture was diluted with EtOAc (40 mL) and the layers wereseparated. To the organic layer was added the filtrate from firstreaction. The layers were separated and the organics were concentratedto give the title compound which was utilized without furtherpurification.

Compound 57.(S)-3-benzyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. Tworeactions were conducted and later combined since both resulted information of product (by HPLC). The first reaction utilized ⅓ of crude57.3 in CH₃OH (1 mL). It was heated in a microwave reactor at 120° C.for 10 min. The remaining ⅔ of crude 57.3 in CH₃OH (2 mL) was heated ina microwave reactor at 120° C. for 20 min. After cooling to ambienttemperature, the reactions were combined and the CH₃OH was removed underreduced pressure. A 50/50 mixture of CH₃CN/H₂O with 0.1% TFA (5 mL) wasadded to the resulting resiude. Solid precipitated and was filtered. Theresulting brown solid was washed with EtOAc to give 7 mg of the titlecompound as a white solid. LC/MS: m/z (ES+) 322 (M+H)⁺. ¹H-NMIR (400MHz, DMSO-d₆): δ ppm 10.05 (br s, 1H), 7.35-7.31 (m, 4H), 7.26-7.16 (m,6H), 6.61 (d, J=7.0 Hz, 1H), 4.79 (s, 2H), 4.52 (quin, J=6.8 Hz, 1H),4.42 (d, J=2.3 Hz, 1H), 1.39 (d, J=6.7 Hz, 3H).

Example 58. Preparation of(S)-3-(2,6-difluorophenyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione(58).

The title compound was synthesized according to a slightly modifiedprocedure as described in Example 50. Here, 1,4-dioxane was utilized asa solvent and the reaction was heated at 110° C. for 16 h. The resultingmixture was cooled and concentrated under reduced pressure. The crudewas purified by preparative RP-HPLC to give 19 mg of the title compoundas a white solid. LC/MS: m/z (ES+) 344 (M+H)⁺. ¹H-NMR (400 MHz,DMSO-d₆): δ ppm 10.44 (br s, 1H), 7.52-7.42 (m, 2H), 7.39-7.36 (m, 3H),7.34-7.16 (m, 3H), 6.91 (br s, 1H), 4.65-4.56 (m, 1H), 4.52 (s, 1H),1.43 (d, J=6.7 Hz, 3H).

Example 59. Preparation of(S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 59.1. 2,6-difluorobenzaldehyde. The title compound wassynthesized according to methods described for the preparation of 51.2.Here, commercially available 2,6-difluorobenzoic acid was utilizedinstead of 2-(4-fluorophenyl)acetic acid.

Compound 59.2. (8)-1-(2,6-difluorophenyl)ethan-1-amine hydrochloride.The title compound was synthesized according to methods described forthe preparation of 5.3. Here, 59.1 was utilized instead of3,5-difluorobenzaldehyde.

Compound 59.(S)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.Reaction of 59.1 with 1.3 was conducted in a similar manner as theprocedure described in Example 51. Here though, the reaction mixture washeated at 130° C. for 5 h. Analysis of the reaction mixture via chiralHPLC revealed non-trivial amounts of the enantiomer. Separation of theenantiomers was performed utilizing preparative chiral HPLC with anisocratic mixture of EtOH: Hexane (1:4) as eluent from a PhenomenexLux-2 5 μ Cellulose-2, 30*150 mm column (40 min run). LC/MS: m/z (ES+)310 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.80 (br s, 1H), 7.45-7.41(m, 1H), 7.18-7.14 (m, 2H), 6.52 (d, J=8.0 Hz, 1H), 4.94-4.88 (m, 1H),4.79 (quint, J=7.6 Hz, 1H), 4.41 (s, 1H), 1.56 (d, J=6.8 Hz, 3H),1.30-1.26 (m, 6H).

Example 60. Preparation of(R)-6-((1-(2,6-difluorophenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione(60R).

The title compound was generated as a by-product of the chemistryconducted in Example 59. It was isolated via preparative chiral HPLCwith an isocratic mixture of EtOH: Hexane (1: 4) as eluent from aPhenomenex Lux-2 5 μ Cellulose-2, 30*150 mm column (40 min run). LC/MS:m/z (ES+) 310 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.98-9.61 (br,1H), 7.45-7.41 (m, 1H), 7.18-7.14 (m, 2H), 6.52 (d, J=8.0 Hz, 1H),4.94-4.88 (m, 1H), 4.79 (quint, J=7.6 Hz, 1H), 4.41 (s, 1H), 1.56 (d,J=6.8 Hz, 3H), 1.30-1.26 (m, 6H).

Example 61. Preparation of(S)-3-isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 61.1. N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide. The titlecompound was synthesized according to methods described for thepreparation of 51.1. Here, commercially available 4-pyridineacetic acidwas utilized instead of 2-(4-fluorophenyl)acetic acid.

Compound 61.2. 1-(pyridin-4-yl)propan-2-one. To a 250-mL 3-neckedround-bottom flask purged and maintained with an inert atmosphere ofargon, was added THF (70 mL) andN-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (7.0 g, 0.039 mol, 1.0equiv). The mixture was cooled to 0° C. and CH₃MgBr (3M in THF, 65 mL,5.0 equiv) was added dropwise. The resulting solution was warmed toambient temperature and stirred for 16 h. The reaction mixture wascooled to 0° C. and quenched by the addition of saturated NH₄Cl (aq, 100mL). The resulting solution was extracted with EtOAc (3×200 mL). Theorganic layers were combined, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure. The crude was purified by flashchromatography (silica gel, CH₂Cl₂/CH₃OH (20:1)) to yield 2.7 g (51%) ofthe title compound as yellow oil. ¹H-NMR (400 MHz,CDCl₃): δ ppm 8.58 (m,2H), 7.17 (d, J=0.4 Hz, 2H), 3.75 (s, 2H), 2.24 (s, 3H).

Compound 61.3.(R)-2-methyl-N-((S)-1-(pyridin-4-yl)propan-2-yl)propane-2-sulfinamide.The title compound was prepared according to procedures described inExample 50 utilizing 61.2 in place of 1-(3-methylphenyl)ethanone. Here,the reduction utilizing L-selectride resulted in isolation of the titlecompound (61.3) (20% enantiomeric excess).

Compound 61.4. (S)-1-(pyridin-4-yl)propan-2-amine. The title compoundwas prepared utilizing a two-step procedure as described in Example 5.First, sulfonamide 61.3 was converted to the hydrochloride salt bytreatment with HCl in 1,4-dioxane (see protocol for Compound 5.3).Subsequent free-basing of the hydrochloride salt (see protocol forCompound 5) resulted in the title compound (˜20% ee).

Compound 61.(S)-3-isopropyl-6-((1-(pyridin-4-yl)propan-2-yl)amino)pyrimidine-2,4(1H,3H)-dione.The title compound was prepared according to the protocol described for51. Here, the reaction mixture was stirred for at 100° C. for 1 h. Thereaction mixture was concentrated under reduced pressure and the residue(100 mg) was purified by Prep-HPLC to give 13.1 mg of the title compoundas a mixture of enantiomers. The enantiomers were (13.1 mg) separated bychiral preparative HPLC with a Chiralpak IC, 2*25 cm, Sum column,utilizing a isocratic mixture of EtOH: Hexane (1:3) as eluent (20 minrun). This resulted in 8.2 mg (8%) of the title compund as a lightyellow solid. LC/MS: m/z (ES+) 289 (M+H)⁺. ¹H-NMR (300 MHz, CD₃OD): δppm 8.41 (d, J=5.7 Hz, 2H), 7.29 (d, J=6.0 Hz, 2H), 5.06-4.96 (m, 1H),4.68 (s, 1H), 3.82-3.75 (m, 1H), 2.87-2.83 (m, 2H), 1.36 (d, J=7.2 Hz,6H), 1.12 (d, J=7.2 Hz, 3H).

Example 62. Preparation of (S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 62.1. (S)-2-(1-(4-(methoxy)phenyl)ethyl)isoindoline-1,3-dione.To phtalimide (1.3 g, 0.0088 mol) in a 2-5 mL microwave vial was added(S)-1-(4-methoxyphenyl)ethan-1-amine (2.20 mL, 0.015 mol) and K2CO3 (1.2g, 0.0087 mol). The reaction mixture capped and heated at 160° C. for 2minutes. The resulting crude solid was suspended in n-BuOH and wasfiltered. The filtrate was put aside. The solid was washed with H₂O andthe filtrate was discarded. The solid was washed with CH₂Cl₂ and theresulting filtrate was partitioned with H₂O. The organics (n-BuOH andCH₂Cl₂ layer) were combined and concentrated. The crude residue waspurified by silica gel column chromatography using CH₂Cl₂ as eluent toyield 1.6 g (64%) of the title compound. LC/MS: m/z (ES+) 282 (M+H)⁺.

Compound 62.2. (8)-2-(1-(4-hydroxyphenyl)ethyl)isoindoline-1,3-dione. Toa stirred solution of 62.1 (640 mg, 2.28 mmol) in CH₂Cl₂ (8 mL) at 0° C.was added BBr₃ (1.0 M in CH₂Cl₂,3 mL, dropwise). The reaction wasallowed to warm to room temperature over 30 minutes. Significantstarting material remained so the reaction was chilled back to 0° C.Additional BBr₃ (2 mL, 1.0 M in CH₂Cl₂) was added and the reaction wasallowed to warm to room temperature over 30 minutes. The reactionmixture was poured over 5% NaHCO₃ (aq) in ice. The layers were separatedand the aqueous layer was further extracted with CH₂Cl₂. The combinedorganics were washed with brine, dried with anhydrous Na₂SO₄ andconcentrated to give 500 mg (82%) of the title compound as a whitesolid. LC/MS: m/z (ES+) 268 (M+H)⁺.

Compound 62.3.(S)-2-(1-(4-(benzyloxy)phenyl)ethyl)isoindoline-1,3-dione. To a stirredsolution of 62.2 (500 mg, 1.87 mmol) in DMF (10 mL) was added K₂CO₃ (560mg, 4.05 mmol, 2.17 equiv.) and benzyl bromide (0.30 mL, 420 mg, 2.45mmol, 1.3 equiv.). The reaction was stirred at 120° C. for 5 h. Thereaction was cooled and filtered. Water was added (20 mL) and EtOAc (60mL) was utilized to extract product. The organic layer was washedsuccessively with H₂O, 10% Na₂CO₃ (aq), H₂O, and brine (2×). Theorganics were dried over anhydrous MgSO₄ and concentrated. The cruderesidue was purified by flash chromatography (silica gel, eluting withCH₂Cl₂) to yield 480 mg (72%) of the title compound. LC/MS: m/z (ES+)358 (M+H)⁺.

Compound 62.4. (8)-1-(4-(benzyloxy)phenyl)ethan-1-amine. To a stirredsolution of 62.3 (480 mg, 1.34 mmol) in a 70/30 EtOH/H₂O mixture (20 mL)was added N₂H₄.H₂O (1.5 mL). The reaction was stirred for 16 h andconcentrated. The resulting material was partitioned between EtOAc and5% Na₂CO₃ (aq). The layers were separated and the EtOAc layer was washedwith brine and concentrated to give 280 mg (92%) of the title compoundwhich was used without further purification. LC/MS: m/z (ES+) 228(M+H)⁺.

Compound 62.(S)-6-((1-(4-(benzyloxy)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.To a 0.5-2.0 mL microwave vial was added 1,4-dioxane (1 mL), 62.4 (280mg, 1.23 mmol), 1.3 (250 mg, 1.33 mmol) and DIEA (400 uL). The reactionmixture was capped, heated at 135° C. in a microwave reactor for 1.5 h,allowed to cool, and then concentrated. The crude reaction mixture wastreated with 50/50 CH₃CN/H₂O (0.1% TFA) which led to precipitation. Thesolid was isloated by filtration and dried to give 45 mg (10%) of awhite solid. LC/MS: m/z (ES+) 380 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δppm 9.73 (br, 1H), 7.43-7.29 (m, 5H), 7.23 (d, J=14.5 Hz, 2H), 6.97 (d,J=14.5 Hz, 2H), 6.42 (d, J=7.0 Hz, 1H), 5.06 (s, 2H), 4.93-4.85 (m, 1H),4.42 (quin, J=6.8 Hz, 1H), 4.32 (d, J=1.6 Hz, 1H), 1.35 (d, J=6.7 Hz,3H), (m, 1H) 1.27-1.23 (m, 6H).

Example 63. Preparation of(S)-6-((1-(4-hydroxyphenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione(63).

To a stirred solution of 62 (43 mg, 0.11 mmol) in CH₃OH (20 mL) wasadded palldium on carbon (50 mg, 10 wt. % loading (dry basis), matrixactivated carbon, wet support, Degussa type). The vessel was purged withnitrogen followed by hydrogen. The reaction mixture was stirred under aH₂ atmosphere for 2 h. After purging the system with nitrogen, themixture was filtered through celite and concentrated. The resultingsolid was dissolved in 8 mL CH₃CN and then 20 mL H₂O (0.1% TFA) wasadded. The solution was frozen and lyophilized to give 29 mg (90%) ofthe title compound as a white solid. LC/MS: m/z (ES+) 290 (M+H)⁺. ¹H-NMR(400 MHz, DMSO-d₆): δ ppm 9.70 (br, 1H), 9.32 (s, 1H), 7.10 (d, J=8.6Hz, 2H), 6.71 (d, J=8.6 Hz, 2H), 6.36 (d, J=7.0 Hz, 1H), 4.92-4.85 (m,1H), 4.37-4.33 (m, 2H), 1.33 (d, J=6.7 Hz, 3H), 1.27-1.23 (m, 6H).

Example 64. Preparation of(R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.

Compound 64.1. (R)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione. Toa 2.0-5.0 mL microwave vial was added (R)-2-amino-2-phenylethan-1-ol(1.53 g, 0.0112 mol) and phthalic anhydride (1.65 g, 0.0112 mol). Thereaction mixture was capped and heated to 150° C. for 2 minutes in amicrowave reactor. The mixture was cooled and diluted with CH₃CN (2 mL),recapped and heated in the microwave reactor a second time at 140° C.for 20 minutes. The volatiles were removed under reduced pressure andthe resulting solid was suspended in EtOAc (50 mL). The organic layerwas washed with 5% NaHCO₃ (aq), H₂O, and brine, dried with anhydrousMgSO₄ and concentrated. The crude residue was purified by flashchromatography (silica gel, eluting with CH₃OH in CH₂Cl₂ (0 to 5%) toyield 2.81 g (94%) of the title compound. LC/MS: m/z (ES+) 268 (M+H)⁺.

Compound 64.2. (R)-2-(2-(benzyloxy)-1-phenylethyl)isoindoline-1,3-dione.The title compound was made in a similar manner as the proceduredescribed for 62.3. However, in this case NaH (60% dispersion in mineraloil, 1.2 equiv.) was used in place of K₂CO₃. Specifically, NaH was addedat 0° C. and stirred at room temperature for 45 minutes. The reactionwas cooled back to 0° C. and then benzyl bromide (1.2 equiv.) was added.A work-up procedure as described for 62.3 followed by flashchromatography (silca gel, eluting with CH₂Cl₂) yielded the titlecompound in 59% yield. LC/MS: m/z (ES+) 358 (M+H)⁺. ¹H-NMR (400 MHz,CDCl₃): δ ppm 7.84-7.79 (m, 2H), 7.72-7.67 (m, 2H), 7.52-7.48 (m, 2H),7.37-7.20 (m, 8H), 5.62 (dd, J=10.2, 5.9 Hz, 1H), 4.63 (t, J=10.2 Hz, 1H), 4.58 (s, 2H), 4.06-4.01 (m, 1H).

Compound 64.3. (R)-2-(benzyloxy)-1-phenylethan-1-amine. The titlecompound was prepared in a similar manner as the procedure described for62.4. LC/MS: m/z (ES+) 228 (M+H)⁺. ¹H-NMR (400 MHz, CDCl₃): δ ppm7.40-7.24 (m, 10H), 4.56 (d, J=2.0 Hz, 2H), 4.25 (dd, J=8.8, 3.7 Hz, 1H), 3.65-3.60 (m, 1H), 3.49-3.44 (m, 1H).

Compound 64.(R)-6-((2-(benzyloxy)-1-phenylethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione.The title compound was prepared in a similar manner as the proceduredescribed for 62. Here though, the reaction was heated at 140° C. for 1h. After cooling, the crude reaction mixture was treated with 50/50CH₃CN/H₂O (0.1% TFA) which led to precipitation. LC/MS: m/z (ES+) 380(M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.01 (br, 1H), 7.36-7.26 (m,10H), 6.62 (d, J=6.7 Hz, 1H), 4.93-4.83 (m, 1H), 4.67-4.62 (m, 1H), 4.50(dd, J=12.0, 2.0 Hz, 2H), 4.30 (s, 1H), 3.68-3.64 (m, 1H), 3.60-3.55 (m,1H) 1.27-1.23 (m, 6H).

Example 65. Preparation of(S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 65.1. 1-(6-methylpyridin-2-yl)urea. To a 25-mL round-bottomflask purged and maintained with an inert atmosphere of argon, was addedurea (1.48 g, 24.64 mmol, 1.00 equiv) and 6-methylpyridin-2-amine (3 g,27.74 mmol, 1.00 equiv). The resulting mixture was stirred for 2 h at145° C. After cooling, the crude product (4 g) was purified usingCombiFlash: Column, C₁₈ silica gel; utilizing a mobile phase of CH₃CN:H₂O=0:100 to CH₃CN: H₂O=50:50 over 40 min. This resulted in theisolation of 1.2 g (32%) of the title compound as a white solid. ¹H-NMR(400 MHz, DMSO-d₆): δ ppm 9.07 (s, 1H), 7.56-7.52 (m, 1H), 7.18-7.14 (m,1H), 6.80-6.75 (m, 1H), 2.36 (s, 3H).

Compound 65.2.1-(6-methylpyridin-2-yl)pyrimidine-2,4,6(1H,3H,5H)-trione. The titlecompound was prepared in a similar manner as the procedure described for1.2. Here though, after stirring overnight at 65° C., the reactionmixture was concentrated under reduced pressure and the crude productwas precipitated from CH₃OH:Et₂O (1:50). The solid was collected byfiltration and dissolved in CH₃OH (50 mL). The pH value of the solutionwas adjusted to 7 with cation ion-exchange resin (Dowex 50WX8-100, 5 g).The solids were filtered and the filtrate was concentrated under reducedpressure resulting in 0.5 g (29%) of the title compound as a whitesolid. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.27 (br s, 1H), 7.69 (t, J=7.6Hz, 1H), 7.17 (d, J=7.6 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 3.18 (s, 2H),2.44 (s, 3H).

Compound 65.3.6-chloro-3-(6-methylpyridin-2-yl)pyrimidine-2,4(1H,3H)-dione. To astirred solution of 65.2 (500 mg, 2.28 mmol, 1.00 equiv) in POCl₃ (5 mL)at 0° C. was added a drop (˜20 μL) of H₂O. The resulting solution waswarmed to room temperature, stirred for 30 min., heated to 70° C. andstirred for 2 h. After cooling, the resulting mixture was concentratedunder reduced pressure. The resulting residue was carefully dissolved in10 mL of ice water. The pH was adjusted to 7 with anion ion-exchangeresin (activated 201×4 (711) strong base styrene anion exchange resin,20 g) and the solids were filtered. The filtrate was concentrated underreduced pressure resulting in 0.2 g (37%) of the title compound as ayellow solid.

Compound 65.(S)-3-(6-methylpyridin-2-yl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.To a 10-mL round-bottom flask purged and maintained with an inertatmosphere of argon was added (S)-α-methylbenzylamine (0.5mL) and 65.3(200 mg, 0.84 mmol, 1.00 equiv). The resulting solution was stirred for3 h at 110° C. After cooling, the resulting mixture was concentratedunder vacuum. The residue (100 mg) was purified by pareparative RP-HPLCwith the following conditions:Column, XBridge Prep C₁₈ OBD Column, Sum,19*150 mm, mobile phase, H₂O with 0.05% NH₄(HCO3) and CH₃CN (15% CH₃CNto 80% in 8 min); This resulted in 28.8 mg (11%) of the title compoundas a white solid. LC/MS: m/z (ES+) 323 (M+H)⁺. ¹H-NMIR (400 MHz,DMSO-d₆): δ ppm 7.76 (t, J=7.6 Hz, 1H), 7.39-7.22 (m, 7H), 7.05 (d,J=7.6 Hz, 1H), 6.82 (br, 1H), 4.63-4.59 (m, 1H), 4.46 (s, 1H), 2.43 (s,3H), 1.44 (d, J=6.4 Hz, 3H).

Example 66. Preparation of(S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 66.1.6-chloro-3-(2,2-difluoroethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)pyrimidine-2,4(1H,3H)-dione.To a stirred solution of 11.1 (130 mg, 0.47 mmol) and Et₃N (0.2 mL) inCH₂Cl₂ (2 mL) at 0° C. was added 2,2-difluoroethyltrifluoromethanesulfonate (0.10 mL). The reaction was warmed to roomtemperature and stirred for 30 minutes. The mixture was concentrated togive the title compound in a crude mixture.

Compound 66.2.6-chloro-3-(2,2-difluoroethyl)pyrimidine-2,4(1H,3H)-dione. Crude 65.1was dissolved in CH₂Cl₂/TFA (1:1, 4 mL) and stirred for 3 h andconcentrated. The resulting material was treated with 5% NaHCO₃ (aq)until the pH was 7. Ethyl acetate was added to the mixture and thelayers were separated. The aqueous layer was concentrated. The resultingsolid was suspended in CH₃CN (15 mL) and was remove by filtration. Thefiltrate was concentrated to give 52 mg of the title compound.

Compound 66.(S)-3-(2,2-difluoroethyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.To 66.2 (52 mg, 0.25 mmol) in 1,4-dioxane (1.5 mL) was added Et₃N (100uL) and (S)-α-methylbenzylamine (188 mg, 1.55 mmol). The reactionmixture was heated in a microwave reactor at 100° C. for 32 minutes,cooled to room temperature, and then concentrated. The resulting residuewas dissolved in a 2:3 CH₃CN/H₂O (10 mL) with 2 drops of TFA (˜40 uL).The mixture was purified by preparative RP-HPLC to provide 8 mg (11%) ofthe title compound as a white solid. LC/MS: m/z (ES+) 296 (M+H)⁺. ¹H-NMR(400 MHz, DMSO-d₆): δ ppm 10.20 (br s, 1H), 7.37-7.32 (m, 4H), 7.26-7.23(m, 1H), 6.71 (d, J=7.0 Hz, 1H), 6.07 (tt, J=56.0, 4.5 Hz, 1H), 4.54(quin, J=6.8 Hz, 1H), 4.43 (d, J=2.3 Hz, 1H), 4.02 (td, J=14.3, 4.7 Hz,2H), 1.40 (d, J=6.7 Hz, 3H).

Example 67. Preparation of(S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione.

Compound 67.1. 2H-1,3-benzodioxole-5-carbaldehyde. To a stirred solutionof 3,4-dihydroxybenzaldehyde (10 g, 72.40 mmol, 1.00 equiv) in DMF (150mL) was added cesium carbonate (35.4 g, 108.31 mmol, 1.50 equiv) anddibromomethane (18.7 g, 107.57 mmol, 1.50 equiv). The resulting solutionwas stirred for 2 h at 110° C. The solution was cooled to roomtemperature and the solid was removed by filtration. The filtrate wasdiluted with H₂O (300 mL). The resulting solution was extracted withEtOAc (2×300 mL). The organic layers were combined, dried over sodiumsulfate, and concentrated under reduced pressure. The crude residue waspurified by silica gel column chromatography, eluted with withEtOAc/petroleum ether (1:9) to afford 8 g (74%) of the title compound asa yellow solid. ¹H-NMR (300 MHz, CDCl₃): δ ppm 9.81 (s, 1H), 7.41 (d,J=8.1 Hz, 1H), 7.34 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 6.08 (s, 2H).

Compound 67.2. (S)-1-(benzo[d][1,3]dioxo1-5-yl)ethan-1-aminehydrochloride. The title compound was synthesized according to methodsdescribed for the preparation of 5.3. Here, 67.1 was utilized instead of3,5-difluorobenzaldehyde. LC/MS: m/z (ES+) 166 (M+H)⁺.

Compound 67.(S)-6-((1-(benzo[d][1,3]dioxol-5-yl)ethyl)amino)-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione.The title compound was synthesized according to methods described inExample 59. Here, 67.2 was utilized instead of(S)-1-(2,6-difluorophenyl)ethan-1-amine hydrochloride and6-chloro-3-(2,2,2-trifluoroethyl)pyrimidine-2,4(1H,3H)-dione wasutilized (synthesized according to methods described in Example 1)instead of 1.3. LC/MS: m/z (ES+) 358 (M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆):δ ppm 10.27 (br s, 1H), 6.94 (d, J=1.2 Hz, 1H), 6.89-6.82 (m, 3H), 6.72(d, J=6.9 Hz, 1H), 5.99 (s, 2H), 4.48-4.40 (m, 4H), 1.38 (d, J=6.9 Hz,3H).

Example 68. Preparation of(S)-3-isopropyl-6-((1-(o-tolyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione(68).

To a stirred solution of (1S)-1-(2-methylphenyl)ethan-1-amine (310 mg,2.29 mmol, 1.50 equiv) in NMP (1 mL) was added proton sponge (491.4 mg,2.30 mmol, 1.50 equiv) and 1.3 (288 mg, 1.53 mmol, 1.00 equiv). Theresulting solution was stirred for 1 hat 130° C. in an oil bath, cooledto room temperature, and then diluted with DMSO (2 mL). The solids werefiltered and the filtrate was purified by Flash-Prep-HPLC with thefollowing conditions: Column: X Bridge C18, 19*150 mm, 5 um; MobilePhase A: H₂O/0.05% TFA, Mobile Phase B: CH₃CN; Flow rate: 20 mL/min;Gradient: 30% B to 70% B in 10 min. This afforded 50 mg of crude productwhich was subsequently separated by chiral preparative HPLC with thefollowing conditions: Column, Chiralpak IC, 2*25 cm, 5um; mobile phase,hexanes and ethanol (9:1, 15 min). This resulted in 35.6 mg (8%) of thetitle compound as a white solid. LC/MS: m/z (ES+) 288 (M+H)⁺. ¹H-NMR(300 MHz, DMSO-d₆): 6 ppm 9.76 (br s, 1H), 7.28 (d, J=7.2 Hz, 1H)7.24-7.14 (m, 3H), 6.48 (d, J=6.3 Hz, 1H), 4.95-4.86 (m, 1H), 4.60(quin, J=6.9 Hz, 1H), 4.19 (s, 1H), 2.34 (s, 3H), 1.37 (d, J=6.6 Hz,3H), 1.27 (d, J=6.9 Hz, 6H).

Example 69. Preparation of(S)-3-cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 69.1. 1-cyclobutylurea. To a stirred solution ofcyclobutanamine (40 g, 562.42 mmol, 1.00 equiv) in CH₂Cl₂ (400 mL) at 0°C. was added trimethylsilyl isocyanate (64.70 g, 561.60 mmol, 1.00equiv.) portionwise. The resulting solution was stirred overnight atroom temperature and was quenched by the addition of CH₃OH (80 mL). Theresulting mixture was stirred for 1 h at room temperature and thenconcentrated under reduced pressure. The residue was washed with Et₂O(2×100 mL) and filtered, which afforded 53 g (83%) of the title compoundas a white solid. ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 6.17 (d, J=9.0 Hz,1H), 5.33 (s, 2H), 3.99-3.91 (m, 1H), 2.16-2.07 (m, 2H), 1.81-1.68 (m,2H), 1.61-1.45 (m, 2H).

Compound 69.2. 1-cyclobutylpyrimidine-2,4,6(1H,3H,5H)-trione. To astirred solution of sodium methoxide (62.43 g, 1.156 mol, 2.40 equiv) inCH₃OH (500 mL) was added dimethyl malonate (76.42 g, 0.578 mol, 1.20equiv) and 69.1 (55 g, 0.48 mol, 1.00 equiv). The resulting solution washeated to 65° C. and stirred overnight. The reaction was cooled andquenched by the addition of H₂O (100 mL). The pH of the solution wasadjusted to 1 with concentrated HCl. The resulting mixture wasconcentrated under reduced pressure. The residue was purified by silicagel column chromatography with CH₂Cl₂/CH₃OH (20:1) as eluent to afford60 g (68%) of the title compound as a white solid. ¹H-NMR (400 MHz,DMSO-d₆): δ ppm 11.20 (s, 1H), 4.95-4.86 (m, 1H), 3.56 (s, 2H),2.72-2.62 (m, 2H), 2.16-2.09 (m, 2H), 1.78-1.60 (m, 2H).

Compound 69.3. 6-chloro-3-cyclobutylpyrimidine-2,4(1H, 3H)-dione. To69.2 (80 g, 0.44 mol, 1.00 equiv) and triethylbenzylammonium chloride(140.2 g, 0.615 mol, 1.40 equiv) was added (300 mL). The reaction wasstirred for 1 h at 65° C. and was then concentrated under reducedpressure. The reaction was quenched by the careful addition of 1 L ofwater/ice and then the pH value of the solution was adjusted to 1 with2N NaOH (aq). The solid was filtered, washed with CH₃OH (300 mL) andEt₂O (2×300 mL), and dried. This resulted in 78 g (89%) of the titlecompound as a light yellow solid. ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 12.23(s, 1H), 5.82 (s, 1H), 5.13-5.01 (m, 1H), 2.87-2.73 (m, 2H), 2.13-2.03(m, 2H), 1.80-1.56 (m, 2H).

Compound 69. (S)-3-cyclobutyl-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a 500-mL round-bottom flask purged and maintained with aninert atmosphere of argon, was added 69.3 (78 g, 388.79 mmol, 1.00equiv) and (S)-α-methylbenzylamine (150 mL, 2.00 equiv). The reactionmixture was stirred for 3 h at 120° C. The reaction mixture was cooledto room temperature, diluted with CH₃OH (1 L) and further cooled to 0°C. The resulting solid was filtered, washed with Et₂O (2×300 mL), anddried under vacuum to afford 57.25 g (52%) of the title compound as awhite solid. LC/MS: m/z (ES+) 286 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δppm 9.94 (br s, 1H), 7.40-7.32 (m, 4H), 7.30-7.26 (m, 1H), 6.40 (br s,1H), 5.19-5.10 (m, 1H), 4.56-4.49 (m, 1H), 4.35 (s, 1H), 2.91-2.81 (m,2H), 2.02-1.95 (m, 2H), 1.76-1.58 (m, 2H), 1.42 (d, J=6.8Hz, 3H).

Example 70. Preparation of(S)-3-isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 70.1.(R,E)-2-methyl-N-(2-(trifluoromethyl)benzylidene)propane-2-sulfinamide.To a 100-mL round-bottom flask purged and maintained with an inertatmosphere of argon, was added CH₂Cl₂ (50 mL),2-(trifluoromethyl)benzaldehyde (2.01 g, 11.54 mmol, 1.00 equiv),(R)-(+)-2-methylpropane-2-sulfinamide (1.68 g, 13.86 mmol, 1.20 equiv),pyridinium p-toluenesulfonate (0.145 g, 0.05 equiv) and magnesiumsulfate (6.93 g, 5.00 equiv). The resulting solution was stirred for 48h at 40° C. The mixture was cooled to room temperature and the solid wasfiltered. The filtrate was concentrated under reduced pressure and theresulting residue was purified by flash column chromatography (silicagel, eluting with EtOAc/petroleum ether (1:20)). This resulted in 0.96 g(30%) the title compound as a light yellow solid. LC/MS: m/z (ES+) 278(M+H)⁺. ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 8.82-8.80 (m, 1H), 8.24 (d,J=7.2 Hz, 1H), 7.95-7.80 (m, 3H), 1.22 (s, 9H).

Compound 70.2.(R)-2-methyl-N-((1S)-1-(2-(trifluoromethyl)phenyl)-ethyl)propane-2-sulfinamide.To a stirred solution of 70.1 (578 mg, 2.08 mmol, 1.00 equiv) in THF (20mL) at −50° C. was added 3 M methylmagnesium bromide in Et₂O (1.4 mL,4.20 mmol, 2.0 equiv) dropwise. The resulting solution was stirred at−50° C. for 2.5 h and at room temperature for an additional 10 h. Thereaction was quenched by the addition of a saturated aqueous NH₄Clsolution (10 mL) and then concentrated under reduced pressure. Theresulting residue was treated with H₂O (50 mL) and extracted with CH₂Cl₂(2×50 mL). The organic layers were combined, dried over Na₂SO₄, andconcentrated under reduced pressure. This resulted in 700 mg (60% de) ofthe title compound as a yellow solid. LC/MS: m/z (ES+) 294 (M+H)⁺.¹H-NMR (300 MHz, DMSO-d₆): δ ppm 7.77-7.74 (m, 1H), 7.67-7.60 (m, 2H),7.43-7.38 (m, 1H), 5.53 (d, J=4.5Hz, 1H), 4.70-4.60 (m, 1H), 1.42 (d,J=6.6 Hz, 3H), 1.02 (s, 9H).

Compound 70.3. (8)-1-(2-(trifluoromethyl)phenyl)ethan-1-aminehydrochloride. To a stirred solution of 70.2 (700 mg, 2.39 mmol, 1.00equiv) in CH₃OH (4 mL) was added 4N HCl in 1,4-dioxane (2 mL) dropwise.The resulting solution was stirred for 1 h at room temperature and thenconcentrated under reduced pressure. Solid was precipitated by theaddition of Et₂O (5 mL). The solid was filtered and dried affording thetitle compound as a white solid (0.32 g, 60%).

Compound 70.4. (8)-1-(2-(trifluoromethyl)phenyl)ethan-1-amine. To a50-mL round-bottom flask was added 70.3 (320 mg, 1.43 mmol, 1.00 equiv)and sodium hydroxide (80 mg, 2.00 mmol, 1.40 equiv) in H₂O (20 mL). Theresulting solution was stirred for 1 h at room temperature and was thenextracted with EtOAc (20 mL). The organic layer was combined andconcentrated under reduced pressure. This afforded 190 mg (70%) of thetitle compound as light yellow oil.

Compound 70.(S)-3-isopropyl-6-((1-(2-(trifluoromethyl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione. To a 10-mL round-bottom flask purged andmaintained with an inert atmosphere of argon, was added NMP (2 mL), 70.4(160 mg, 0.85 mmol, 1.00 equiv), 1.3 (160 mg, 0.85 mmol, 1.00 equiv),and proton sponge (273 mg, 1.28 mmol, 1.5 equiv.). The resultingsolution was stirred for 4 h at 130° C. The crude product (200 mg) waspurified by chiral preparative HPLC with the following conditions:Column, Phenomenex Lux-2 5u Cellulose-2, 30*150 mm; mobile phase,Hex-HPLC and ethanol-HPLC (hold 20% ethanol-HPLC in 14 min); Detector,uv 254/220 nm. 160 mg crude product was obtained. The obtained material(60 mg) was further purified using chiral preparative HPLC withfollowing conditions: Column: Phenomenex Lux-2 5 μ Cellulose-2 30*150mm; Mobile Phase and Gradient: Hex: EtOH=80:20; Retention Time (Peak 2)(min):11.106. This resulted in 30 mg of the title compound as a whitesolid. LC/MS: m/z (ES+) 342 (M+H)⁺. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm9.84 (br, 1H), 7.78-7.68 (m, 3H), 7.56-7.52 (m, 1H), 6.75 (br s, 1H),4.93-4.86 (m, 1H), 4.68-4.63 (m, 1H), 4.13 (s, 1H), 1.46 (d, J=6.8 Hz,3H), 1.25 (d, J=7.2 Hz, 6H).

Example 71. Preparation of(S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione.

Compound 71.1. 1-(1-methylcyclopropyl)urea. To a stirred solution of1-methylcyclopropan-1-amine hydrochloride salt (429 mg, 3.99 mmol, 1.00equiv) and triethylamine (268 mg, 2.65 mmol, 1.00 equiv) in CH₂Cl₂ (6mL) was added trimethylsilyl isocyanate (366 mg, 3.18 mmol, 1.20 equiv).The resulting mixture was stirred at room temperature overnight and wasquenched by the dropwise addition of CH₃OH (2 mL) at 0° C. The resultingsolution warmed to room temperature and stirred for an additional 1 h.The resulting mixture was concentrated under reduced pressure. The crudeproduct was precipitated from CH₃OH:Et₂O (1:40) affording 300 mg (66%)of the title compound as a white solid.

Compound 71.2. 1-(1-methylcyclopropyl)pyrimidine-2,4,6(1H,3H)-trione. Toa stirred solution of 71.1 (320 mg, 2.80 mmol, 1.0 equiv) in CH₃OH (2mL) was added sodium methoxide (390 mg, 7.2 mmol, 2.5 equiv) anddimethyl malonate (380 mg, 2.88 mmol, 1.0 equiv). The resulting solutionwas stirred overnight at 65° C. After cooling, the reaction was quenchedby the addition of H₂O (100 mL). The pH of the solution was adjusted to2 with concentrated HCl and the resulting mixture was concentrated underreduced pressure. The crude residue was purified by silica gel columnchromatography with EtOAc/petroleum ether (1:3) as eluent. This afforded100 mg (20%) of the title compound as a white solid. ¹H-NMR (300 MHz,CDCl₃): 6 ppm 8.04 (br, 1H), 3.61 (s, 2H), 1.41 (s, 3H), 1.00-0.86 (m,4H).

Compound 71.3.6-chloro-3-(1-methylcyclopropyl)pyrimidine-2,4(1H,3H)-dione. To 71.2(100 mg, 0.55 mmol, 1.00 equiv) and triethylbenzylammonium chloride (180mg, 0.79 mmol, 1.00 equiv) was added POCl₃ (2 mL). The resultingsolution was stirred for 3 h at 50° C. and then concentrated underreduced pressure. The residue was carefully quenched by the addition of10 mL of water/ice and was extracted with EtOAc (2×30 mL). The organiclayers were combined and concentrated under reduced pressure. The cruderesidue was purified by silica gel column chromatography withCH₂Cl₂/CH₃OH (10:1) as eluent to afford 40 mg (36%) of the titlecompound as a yellow solid.

Compound 71.(S)-3-(1-methylcyclopropyl)-6-((1-phenylethyl)amino)pyrimidine-2,4(1H,3H)-dione. To 71.3 (40 mg, 0.20 mmol, 1.00 equiv) was added(S)-α-methylbenzylamine (0.5 mL). The reaction mixture was stirred for 2h at 130° C. and then was concentrated under reduced pressure. Theresulting residue was purified by preparative RP-HPLC with the followingconditions: Column: X Bridge C18, 19*150 mm, 5 um; Mobile Phase A:H₂O/0.05% TFA, Mobile Phase B: CH₃CN; Flow rate: 20 mL/min; Gradient:30% B to 70% B in 10 min. This afforded 15.1 mg (27%) of the titlecompound as a white solid. LC/MS: m/z (ES+) 286 (M+H)⁺. ¹H-NMR (300 MHz,CD₃CN): δ ppm 8.41 (br, 1H), 7.42-7.29 (m, 5H), 5.79 (br, 1H), 4.48-4.44(m, 1H), 4.30 (s, 1H), 1.47 (d, J=6.9 Hz, 3H), 1.27 (s, 3H), 0.87-0.77(m, 4H).

Example 72. Preparation of Additional Pyrimidine Dione Compounds.

The compounds in Table 1B were prepared according to the examples asdescribed above (exemplary methods provided as ‘Reference. Ex. No.’)

Compound No. Observed Mass and/or Structure Reference Ex. No. ¹H NMR

72 17 340 (M + H)⁺ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.89 (br s, 1H),9.54 (br s, 1H), 8.22 (br s, 1H) 7.82 (br s, 1H), 7.75 (s, 1H) 7.66-7.54(m, 2H), 7.48 (d, J = 7.5 Hz, 1H), 6.60-6.58 (m, 1H), 4.90-4.83 (m, 1H),4.55- 4.48 (m, 1H), 4.30 (s, 1H), 1.42 (d, J = 6.9 Hz, 3H), 1.27-1.21(m, 6H).

73 15 310 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.20 (m, 1H), 9.04(br s, 1H), 7.57 (m, 1H) 7.38-7.32 (m, 4H), 7.26-7.21 (m, 1H), 6.76 (m,1H), 4.69-4.62 (m, 1H), 4.46 (s, 1H), 1.40 (d, J = 6.8 Hz, 3H).

74 15 310 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.56 (m, 1H), 8.49(m, 1H), 8.37 (m, 1H), 7.37-7.31 (m, 4H), 7.26-7.22 (m, 1H), 6.68 (m,1H), 4.71-4.65 (m, 1H), 4.34 (s, 1H), 1.37 (d, J = 6.8 Hz, 3H).

75 15 310 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.60 (m, 1H), 8.57(m, 1H), 8.49 (br s, 1H), 7.39-7.32 (m, 4H), 7.26-7.22 (m, 1H), 6.68 (m,1H), 4.69-4.64 (m, 1H), 4.41 (s, 1H), 1.39 (d, J = 6.8 Hz, 3H).

76 5 and 58 275 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.70 (br, 1H),8.60 (d, J = 2.0 Hz, 1H) 8.50 (dd, J = 4.8, 1.6 Hz, 1H), 7.76 (d, J =8.0 Hz, 1H), 7.41 (dd, J = 7.6, 4.8 Hz, 1H), 6.67 (br s, 1H), 4.94-4.88(m, 1H), 4.62- 4.58 (m, 1H), 4.38 (s, 1H), 1.45 (d, J = 6.4 Hz, 3H),1.30-1.28 (m, 6H).

77 15 312 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.69 (br s, 1H),7.65 (s, 1H), 7.40- 7.20 (m, 7H), 4.52 (quin, J = 6.8 Hz, 1H), 4.40 (s,1H), 3.30 (br s, 3H), 1.39 (d, J = 7.0 Hz, 3H).

78 1 302 (M + H)+ ¹H-NMR (400 MHz, CDCl₃): δ ppm 10.58 (br s, 1H),7.36-7.23 (m, 5H), 5.16 (m, 2H), 4.69 (s, 1H), 4.26 (m, 1H), 1.82-1.71(m, 2H), 1.44-1.38 (m, 6H), 1.36-1.25 (m, 2H), 0.92 (t, J = 8.0 Hz, 3H).

79 11 316 (M + H)+ ¹H-NMR (400 MHz, CD₃CN): δ ppm 7.30-7.20 (m, 4H),7.16-7.11 (m, 1H), 6.32 (m, 1H), 4.69-4.62 (m, 1H), 4.43 (quin, J = 6.7Hz, 1H), 4.29 (s, 1H), 4.00 (t, J = 10.5 Hz, 1H), 3.67-3.59 (m, 1H),3.44-3.40 (m, 1H), 3.14-3.08 (m, 1H), 2.48- 2.38 (m, 1H), 1.56-1.45 (m,3H), 1.38 (d, J = 6.8 Hz, 3H).

80 1 300 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.82 (br s, 1H),7.41-7.19 (m, 5H), 6.50 (d, J = 6.7 Hz, 1H), 5.05-5.01 (m, 1H), 4.50-4.46 (m, 1H), 4.34 (s, 1H), 2.01-1.84 (m, 2H), 1.83- 1.64 (m, 2H),1.63-1.51 (m, 2H), 1.49-1.34 (m, 5H).

81 5 302 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.39-7.35 (m, 2H),7.30-7.28 (m, 3H), 5.06-5.00 (m, 1H), 4.53 (s, 1H), 4.12 (d, J = 7.2 Hz,1H), 2.10-2.01 (m, 1H), 1.40-1.37 (m, 6H), 1.02 (d, J = 6.8 Hz, 3H),0.93 (d, J = 6.8 Hz, 3H).

82 7 302 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD): δ ppm 7.43-7.33 (m, 4H),7.30-7.26 (m, 1H), 4.82-4.75 (m, 1H), 4.54- 4.49 (m, 2H), 2.74-2.65 (m,2H), 2.15-2.05 (m, 2H), 1.93-1.79 (m,2H), 1.61-1.57 (m, 2H), 1.51 (d, J= 6.8 Hz, 3H).

83 1 302 (M + H)⁺ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.73 (br s, 1H),7.40-7.22 (m, 5H), 6.50 (d, J = 5.1 Hz, 1H), 4.57-4.44 (m, 2H), 4.34 (brs, 1H), 1.90 (ddd, J = 13.3, 9.8, 7.4 Hz, 2H), 1.61-1.50 (m, 2H), 1.38(d, J = 6.7 Hz, 3H), 0.74-0.60 (m, 6H).

84 12 419 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.88 (br s, 1H),7.45-7.41 (m, 3H), 7.37-7.29 (m, 6H), 7.27- 7.22 (m, 1H), 6.54 (d, J =6.7 Hz, 1H), 4.84-4.79 (m, 1H), 4.52-4.47 (m, 1H), 4.36 (d, J = 2.4 Hz,1H), 3.57 (m, 2H), 3.05 (m, 2H), 2.38 (m, 2H), 1.50 (m, 2H), 1.38 (d, J= 6.7 Hz, 3H).

85 1 302 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.73 (br s, 1H),7.31-7.22 (m, 2H), 7.21-7.12 (m, 3H), 5.93 (d, J = 8.2 Hz, 1H),5.00-4.87 (m, 1H) 4.44 (s, 1H), 4.30 (s, 1H), 3.37-3.31 (m, 1H),2.65-2.53 (m, 2H), 1.70 (dtd, J = 9.0, 6.9, 6.9, 2.0 Hz, 1H), 1.29 (d, J= 7.0 Hz, 6H), 1.11 (d, J = 6.3 Hz, 3H).

86 11 304 (M + H)⁺ ¹H-NMR (400 MHz, CD₃OD + CDCl₃): 7.22- 7.15 (m, 2H),7.13-7.07 (m, 3H), 6.28 (d, J = 6.1 Hz, 1H), 4.44 (s, 1H), 4.38 (s, 2H),4.30-4.23 (m, 1H), 3.55 (s, 3H), 1.35 (d, J = 6.8 Hz, 3H).

90 1 288 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.77 (br s, 1H),7.32-7.26 (m, 2H), 7.23-7.12 (m, 3H), 5.85 (d, J = 7.9 Hz, 1H),4.97-4.87 (m, 1H), 4.55 (s, 1H), 3.77-3.65 (m, 1H), 2.76- 2.68 (m, 2H),1.27 (d, J = 7.0 Hz, 6H), 1.05 (d, J = 6.7 Hz, 3H).

91 53 380 (M + H)+ ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.77 (br s, 1H),7.33-7.23 (m, 10H), 5.23 (br s, 1H), 4.67 (br s, 1H), 4.57 (d, J = 12.0Hz, 1H), 4.47 (d, J = 12.0 Hz, 1H), 4.44-4.37 (m, 1H), 4.09 (t, J = 9.2Hz, 1H), 3.63 (dd, J = 9.8, 5.9 Hz, 1H), 1.48 (d, J = 6.7 Hz, 3H), 1.35(d, J = 7.0 Hz, 3H).

92 54 290 (M + H)+ ¹H-NMR (400 MHz, CDCl₃): δ ppm 9.68 (s, 1H),7.41-7.22 (m, 5H), 5.62 (s, 1H), 5.08 (td, J = 7.3, 2.9 Hz, 1H), 4.67(s, 1H), 4.48-4.35 (m, 1H), 3.98 (dd, J = 11.9, 7.6 Hz, 1H), 3.75 (dd, J= 11.7, 3.1 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.36 (d, J = 7.0 Hz, 3H).

93 1 290 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.01 (d, J = 2.0 Hz,1H), 7.37- 7.23 (m, 5H), 6.61 (d, J = 6.3 Hz, 1H), 5.19 (t, J = 5.1 Hz,1H), 4.93-4.83 (m, 1H), 4.40-4.33 (m, 1H), 4.24 (d, J = 2.4 Hz, 1H),3.66 (dt, J = 11.1, 4.7 Hz, 1H), 3.52-3.44 (m, 1H), 1.25 (dd, J = 6.9,2.2 Hz, 6H).

94 1 and 50 328 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆ @ 75° C.): δ ppm 9.91(br s, 1H), 7.44- 7.23 (m, 5H), 6.58 (br s, 1H), 5.52 (br s, 1H), 4.59-4.51 (m, 1H), 4.46 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.43 (d, J =7.0 Hz, 3H).

95 1 and 50 328 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆ @ 75° C.): δ ppm 9.91(br s, 1H), 7.44- 7.23 (m, 5H), 6.58 (br s, 1H), 5.52 (br s, 1H), 4.59-4.51 (m, 1H), 4.46 (br s, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.43 (d, J =7.0 Hz, 3H).

99 1 342 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆ @ 50° C.): δ ppm 9.79 (br s,1H), 7.46-7.23 (m, 5H), 6.51 (d, J = 6.7 Hz, 1H), 5.13 (br s, 1H), 4.50(quin, J = 6.9 Hz, 1 H), 4.37 (s, 1H), 3.15-3.01 (m, 1H), 2.60- 2.50 (m,1H), 1.40 (d, J = 6.7 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H).

100 1 and 50 314 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.32 (br s,1H), 7.40-7.34 (m, 4H), 7.29-7.25 (m, 1H), 6.81 (d, J = 6.6 Hz, 1H),4.60-4.54 (m, 1H), 4.49- 4.40 (m, 3H), 1.42 (d, J = 6.6 Hz, 3H).

101 1 and 50 288 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.50 (br s,1H), 7.56-7.44 (m, 4H), 7.38-7.24 (m, 1H), 6.41 (d, J = 6.4 Hz, 1H),4.45 (q, J = 6.8 Hz, 1H), 4.25 (s, 1H), 1.54 (s, 9H), 1.38 (d, J = 6.8Hz, 3H).

102 57 290 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.31 (br s, 1H),7.35-7.23 (m, 5H), 5.72 (d, J = 4.7 Hz, 1H), 4.67 (s, 1H), 4.40 (quin, J= 6.6 Hz, 1H), 4.05 (t, J = 5.7 Hz, 2H), 3.56 (t, J = 5.7 Hz, 2H), 3.27(s, 3H), 1.46 (dd, J = 6.7, 1.6 Hz, 3H).

103 1 and 59 342 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆, @ 75° C.): δ ppm9.91 (br s, 1H), 7.37-7.24 (m, 5H), 6.59 (br s, 1H), 5.51 (br s, 1H),4.45 (br s, 1H), 4.31 (q, J = 6.9 Hz, 1H), 1.83-1.67 (m, 2H), 1.52 (d, J= 7.4 Hz, 3H), 0.86 (t, J = 7.4 Hz, 3H).

104 1 and 58 300 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.80 (br s,1H), 7.37-7.31 (m, 4H), 7.27-7.22 (m, 1H), 6.52 (br, 1H), 4.48 (q, J =6.7 Hz, 1H), 4.32 (br s, 1H), 3.93 (br, 1H), 1.62 (br, 1H), 1.38 (d, J =6.7 Hz, 3H), 1.33 (d, J = 7.0 Hz, 3H), 0.48-0.41 (m, 1H), 0.27-0.21 (m,1H), 0.14 (dq, J = 9.4, 4.8 Hz, 1H), 0.02 (m, 1H).

105 1 and 58 300 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.81 (br s,1H), 7.37-7.30 (m, 4H), 7.26-7.22 (m, 1H), 6.53 (d, J = 5.9 Hz, 1H),4.48 (q, J = 6.8 Hz, 1H), 4.32 (d, J = 1.6 Hz, 1H), 3.85 (m, 1H), 1.61(m, 1H), 1.38 (d, J = 7.0 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H), 0.49-0.42(m, 1H), 0.28-0.22 (m, 1H), 0.17-0.12 (m, 1H), 0.01- (-) 0.05, (m, 1H).

106 8 300 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.96 (br s, 1H),7.36-7.24 (m, 5H), 6.48 (d, J = 6.3 Hz, 1H), 4.40 (s, 1H), 4.36-4.27 (m,1H), 3.63 (q, J = 6.6 Hz, 2H), 2.67-2.50 (partially obscured m, 1H)2.02-1.95 (m, 1H), 1.90-1.78 (m, 4H), 1.66-1.57 (m, 1H), 0.98 (t, J =6.6 Hz, 3H).

107 67 and 59 318 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.76 (br s,1H), 6.92 (d, J = 1.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 6.80 (dd, J =6.0, 1.8 Hz, 1H), 6.44 (d, J = 7.2 Hz, 1H), 5.99 (s, 2H), 4.93-4.88 (m,1H), 4.41- 4.35 (m, 2H), 1.35 (d, J = 6.6 Hz, 3H) 1.28 (d, J = 1.2 Hz,3H) 1.26 (d, J = 1.2 Hz, 3H).

108 67 and 59 304 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.93 (br s,1H), 6.92 (d, J = 1.5 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 6.82-6.79 (m,1H), 6.48 (d, J = 7.2 Hz, 1H), 5.99 (s, 2H), 4.45-4.39 (m, 2H), 3.65 (q,J = 6.6 Hz, 2H), 1.36 (d, J = 6.9 Hz, 3H) 0.99 (t, J = 6.9 Hz, 3H).

109 1, 5 and 7 328 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.28 (brs, 1H), 7.39-7.24 (m, 5H), 6.81 (d, J = 6.6 Hz, 1H), 4.47-4.33 (m, 4H),1.80-1.67 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H).

110 1 and 50 286 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.01 (br s,1H), 7.39-7.33 (m, 4H), 7.30-7.23 (m, 1H), 6.60 (d, J = 6.0 Hz, 1H),4.52 (q, J = 6.6 Hz, 1H), 4.38 (s, 1H), 3.49 (d, J = 6.9 Hz, 2H), 1.40(d, J = 6.9 Hz, 3H) 1.08-1.00 (m, 1H), 0.37-0.33 (m, 2H), 0.28-0.23 (m,2H).

111 7 and 59 340 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.29 (br s,1H), 7.37-7.33 (m, 4H), 7.30-7.25 (m, 1H), 6.98 (d, J = 5.6 Hz, 1H),4.42 (q, J = 9.2 Hz, 2H), 4.35 (d, J = 1.6 Hz, 1H), 3.89-3.85 (m, 1H),1.24- 1.15 (m, 1H) 0.61-0.56 (m, 1H), 0.50-0.33 (m, 3H).

112 8 and 59 354 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.27 (br s,1H), 7.45-7.25 (m, 5H), 6.73 (br s, 1H), 4.46- 4.35 (m, 4H), 2.67-2.50(partially obscured m, 1H), 2.04-2.01 (m, 1H), 1.90- 1.79 (m, 4H),1.68-1.62 (m, 1H).

113 15 306 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆, @ 75° C.): δ ppm 9.86 (brs, 1H), 7.39-7.31 (m, 4H), 7.29-7.25 (m, 1H), 6.48 (d, J = 6.7 Hz, 1H),5.00-4.91 (m, 1H), 4.78 (m, 1H), 4.56-4.50 (m, 1H), 4.45-4.38 (m, 2H),3.76-3.70 (m, 2H), 1.42 (d, J = 7.4 Hz, 3H).

114 1 and 51 360 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆, @ 75° C.): δ ppm9.86 (br s, 1H), 7.25 (dd, 8.4, 5.7 Hz, 2H), 7.10-7.04 (m, 2H), 5.94 (brs, 1H), 5.52 (br s, 1H), 4.62 (br s, 1H), 3.79-3.71 (m, 1H), 2.76 (d, J= 6.7 Hz, 2H), 1.55 (d, J = 7.0 Hz, 3H), 1.11 (d, J = 6.3 Hz, 3H).

115 62 290 (M + H)+

116 62 290 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.83 (br s, 1H),9.68 (br s, 1H), 7.14 (dd, J = 7.4, 1.6 Hz, 1H), 7.05 (td, J = 7.6, 1.6Hz, 1H), 6.82-6.74 (m, 2H), 6.40 (d, J = 7.0 Hz, 1H), 4.92-4.85 (m, 1H),4.60 (quin, J = 6.9 Hz, 1H), 4.30 (d, J = 2.4 Hz, 1H), 1.35 (d, J = 6.7Hz, 3H), 1.27-1.22 (m, 6H).

117 1 and 59 340 (M + H)+ ¹H-NMR (300 MHz, CDCl₃: δ ppm 10.40 (br s,1H), 7.44-7.26 (m, 5H), 6.13 (br s, 1H), 4.80 (br s, 1H), 4.45 (m, 1H),1.76- 1.52 (m, 5H), 1.35-1.27 (m, 2H).

118 1 and 51 376 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.27 (br s,1H), 7.29-7.22 (m, 3H), 7.15-7.10 (m, 2H), 7.01 (dd, J = 8.2, 2.3 Hz,2H), 6.12 (br s, 1H), 4.72 (d, J = 2.0 Hz, 1H), 3.79- 3.71 (m, 1H), 2.76(d, J = 6.7 Hz, 2H), 1.09 (d, J = 6.7 Hz, 3H).

119 5 and 59 354 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.84 (br s,1H), 7.43 (d, J = 1.2 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.21 (dd, J =8.4, 1.2 Hz, 1H), 6.54 (d, J = 6.8 Hz, 1H), 4.90 (q, J = 6.8 Hz, 1H),4.55-4.52 (m, 1H), 4.34 (d, J = 2.0 Hz, 1H), 1.39 (d, J = 6.8 Hz, 3H)1.31-1.26 (m, 6H).

120 5 and 59 308 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 9.87 (m, 1H),7.48-7.28 (m, 4H), 6.66 (d, J = 6.6 Hz, 1H), 4.93-4.84 (m, 1H), 4.70(quin, J = 6.6 Hz, 1H), 4.08 (s, 1H), 1.41 (d, J = 6.6 Hz, 3H),1.28-1.24 (m, 6H).

121 5 304 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.68 (m, 1H),7.25-7.21 (m, 2H), 6.91-6.87 (m, 2H), 6.43 (m, 1H), 4.92-4.85 (m, 1H),4.41 (quin, J = 6.7 Hz, 1H), 4.32 (s, 1H), 3.71 (s, 3H), 1.35 (d, J =6.7 Hz, 3H), 1.27-1.23 (m, 6H).

122 7 and 59 286 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 7.38- 7.33(m, 4H), 7.28-7.25 (m, 1H), 6.80 (br s, 1H), 4.24 (s, 1H), 3.82-3.78 (m,1H), 3.63 (q, J = 6.8 Hz, 2H), 1.17-1.13 (m, 1H), 0.97 (t, J = 6.8 Hz,3H), 0.59-0.54 (m, 1H), 0.47- 0.32 (m, 3H).

123 1 and 59 294 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.00 (br s,1H), 7.44 (s, 1H), 7.42-7.30 (m, 3H), 6.61 (d, J = 6.6 Hz, 1H),4.57-4.53 (m, 1H), 4.38 (d, J = 1.8 Hz, 1H), 3.65 (q, J = 6.9 Hz, 2H),1.39 (d, J = 6.9 Hz, 3H), 0.99 (t, J = 7.2 Hz, 3H).

124 1 and 59 328 (M + H) ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 7.75 (s, 1H),7.72-7.59 (m, 3H), 6.99 (br s, 1H), 4.68-4.62 (m, 1H), 4.38 (s, 1H),3.65 (q, J = 6.6 Hz, 2H), 1.42 (d, J = 6.6 Hz, 3H), 1.01 (t, J = 4.5 Hz,3H).

125 1 and 59 304 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.01 (br s,1H), 7.42 (dd, J = 7.8, 6.0 Hz, 1H), 7.20 (d, J = 7.5 Hz, 2H), 7.12-7.06(m, 1H), 6.62 (d, J = 7.2 Hz, 1H), 4.56 (quin, J = 6.9 Hz, 1H), 4.39 (s,1H), 3.49 (d, J = 6.9 Hz, 2H), 1.40 (d, J = 6.6 Hz, 3H), 1.07-0.99 (m,1H), 0.37- 0.34 (m, 2H), 0.30-0.22 (m, 2H).

126 1 and 59 354 (M + H)+ ¹H-NMR (300 MHz, CD₃OD): δ ppm 7.73-7.50 (m,4H), 4.63 (q, J = 6.9 Hz, 1H), 3.62 (d, J = 7.2 Hz, 2H), 1.50 (d, J =6.9 Hz, 3H) 1.17-1.10 (m, 1H), 0.45-0.39 (m, 2H), 0.32- 0.26 (m, 2H).

127 1 and 59 304 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.01 (br s,1H), 7.45 (s, 1H), 7.42-7.30 (m, 3H), 6.64 (d, J = 6.9 Hz, 1H),4.58-4.53 (m, 1H), 4.39 (s, 1H), 3.50 (d, J = 7.2 Hz, 2H), 1.40 (d, J =6.6 Hz, 3H) 1.07- 1.03 (m, 1H), 0.37-0.31 (m, 2H), 0.25-0.22 (m, 2H).

128 3 388 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.50 (br s, 1H),7.52-7.22 (m, 3H), 4.87-4.72 (m, 1H), 4.52- 4.41 (m, 1H), 1.60-1.48 (m,3H), 1.41-1.27 (m, 6H).

129 1 and 59 292 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.00 (br s,1H), 7.40 (dt, J = 7.8 Hz, 0.6 Hz, 1H), 7.26 (d, J = 7.8 Hz, 2H),7.09-7.06 (m, 1H), 6.60 (d, J = 6.9 Hz, 1H), 4.46 (q, J = 6.6 Hz, 1H),4.38 (s, 1H), 3.60-3.55 (m, 2H), 1.47- 1.39 (m, 5H), 0.79 (t, J = 7.5Hz, 3H).

130 1 and 59 308 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.01 (br s,1H), 7.44 (t, J = 0.9 Hz, 1H), 7.41-7.38 (m, 1H), 7.34-7.31 (m, 2H),6.62 (d, J = 5.1 Hz, 1H), 4.55 (q, J = 6.7 Hz, 1H), 4.38 (s, 1H), 3.54(dd, J = 6.0, 5.7 Hz, 2H), 1.47-1.39 (m, 5H), 0.84 (t, J = 7.5 Hz, 3H).

131 1 and 59 342 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.05 (br s,1H), 7.74 (s, 1H), 7.68-7.56 (m, 3H), 6.69 (d, J = 6.4 Hz, 1H),4.70-4.63 (m, 1H), 4.40 (s, 1H), 3.59-3.54 (m, 2H), 1.49- 1.40 (m, 5H),0.86 (t, J = 6.0 Hz, 3H).

132 1 304 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.85 (br s, 1H),7.37-7.33 (m, 2H), 7.18-7.13 (m, 2H), 6.52 (d, J = 7.4 Hz, 1H),5.14-5.05 (m, 1H), 4.50 (quin, J = 6.8 Hz, 1H), 4.31 (s, 1H), 2.84-2.78(m, 2H), 1.97- 1.91 (m, 2H), 1.70-1.54 (m, 2H), 1.36 (t, J = 6.7 Hz,3H).

133 1 290 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.83 (br s, 1H),9.68 (br s, 1H), 7.14 (dd, J = 7.4, 1.6 Hz, 1H), 7.07-7.03 (m, 1H),6.81-6.74 (m, 2H), 6.42 (d, J = 7.0 Hz, 1H), 4.92-4.85 (m, 1H), 4.60(quin, J = 6.8 Hz, 1H),4.31 (d, J = 2.3 Hz, 1H), 1.35 (d, J = 7.0 Hz,3H), 1.27-1.22 (m, 6H).

134 1 296 (M + H)+ ¹H-NMR (300 MHz, DMSO-d₆): δ ppm 10.03 (br s, 1H),7.48-7.39 (m, 2H), 7.23-7.20 (m, 1H), 6.60 (d, J = 5.1 Hz, 1H) 4.58-4.53(m, 1H), 4.38 (s, 1H), 3.66 (q, J = 5.1 Hz, 2H), 1.39 (d, J = 5.1 Hz,3H), 0.99 (t, J = 5.1 Hz, 3H).

135 1 306 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.95 (br s, 1H),7.36 (dd, J = 9.0, 5.5 Hz, 2H), 7.18-7.14 (m, 2H), 6.54 (d, J = 7.0 Hz,1H) 4.66 (br s, 1H), 4.54- 4.49 (m, 1H), 4.34 (s, 1H), 1.97-1.86 (m,1H), 1.65- 1.55 (m, 1H), 1.38 (d, J = 6.8 Hz, 3H), 1.23 (d, J = 6.8 Hz,3H), 0.70 (t, J = 6.8 Hz, 3H).

136 1 292 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 9.95 (br s, 1H),7.36 (dd, J = 9.0, 5.5 Hz, 2H), 7.18-7.14 (m, 2H), 6.54 (d, J = 7.0 Hz,1H) 4.56-4.49 (m, 1H), 4.35 (d, J = 2.3 Hz, 1H), 3.57-3.53 (m, 2H),1.44- 1.36 (m, 5H), 0.77 (t, J = 7.4 Hz, 3H).

137 65 327 (M + H)+ ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.36 (br s, 1H),8.09 (q, J = 8.0 Hz, 1H), 7.39-7.35 (m, 4H), 7.30-7.22 (m, 3H), 6.87 (m,1H), 4.61 (quin, J = 6.8 Hz, 1H), 4.49 1H), 1.44 (d, J = 6.8 Hz, 3H).

Example 73. Myosin inhibition Assay

Small molecule agents were assessed for their ability to inhibit theenzymatic activity of bovine cardiac myosin using a biochemical assaythat couples the release of ADP (adenosine diphosphate) from cardiacmyosin to an enzymatic coupling system consisting of pyruvate kinase andlactate dehydrogenase (PK/LDH) and monitoring the absorbance decrease ofNADH (at 340 nm) as a function of time. PK converts ADP to ATP(adenosine triphosphate) by converting PEP (phosphoenolpyruvate) topyruvate. Pyruvate is then converted to lactate by LDH by convertingNADH (nicotinamide adenine dinucleotide) to NAD (oxidized nicotinamideadenine dinucleotide). The source of cardiac myosin was from bovineheart in the form of skinned myofibrils. Prior to testing small moleculeagents, the bovine myofibrils were assessed for their calciumresponsiveness and the calcium concentration that achieves either a 50%(pCa₅₀) or 75% (pCa₇₅) activation of the myofibril system was chosen asthe final condition for assessing the inhibitory activity of the smallmolecule agents. All enzymatic activity was measured in a bufferedsolution containing 12 mM PIPES (piperazine-N,N′-bis(2-ethanesulfonicacid), 2 mM magnesium chloride at pH 6.8 (PM12 buffer). Final assayconditions were 1 mg/mL of bovine cardiac myofibrils, 0.4 mM PK/LDH, 50uM ATP, 0.1 mg/mL BSA (bovine serum albumin), 10 ppm antifoam, 1 mM DTT,0.5 mM NADH, 1.5 mM PEP at the desired free calcium concentrationrequired to achieve either 50% or 75% activation of the myofibrils.

A dilution series of compound was created in DMSO such that the finaldesired concentration of compound would be achieved in a volume of 100μL with a fixed DMSO concentration of 2% (v/v). Typically 2 μL of thedilution series were added to 96 well plate to achieve an 8 or 12 pointdose response. Following the addition of 50 μL of a solution containingbovine cardiac myofibrils, PK/LDH and a solution of calcium (thatachieved the desired activation), the enzymatic reaction was startedwith the addition of 50 μL of a solution containing ATP, PEP and NADH.The reaction progress was followed in a Molecular Devices M5e platereader at ambient temperature using clear half area plates. The platereader was configured to read absorbance at 340 nm in kinetics mode for15 minutes. Data were recorded as the slope of the absorbance responseto time. The slopes of the absorbance response as a function of timewere normalized to slopes on the plate containing DMSO. This normalizedrate was then plotted as a function of small molecule concentration andthe data was fitted to a four-parameter fit using GraphPad Prism. Themidpoint of this plot is the IC₅₀ and is the concentration at whichfifty percent of the total response is inhibited. Any agent that failedto achieve a fifty percent inhibition at the highest concentrationtested was reported as an IC₅₀ greater than the highest concentrationtested (ie. IC_(50>25) uM).

TABLE 2 Myosin Inhibition Activity of Selected Compounds^(a) BiochemicalBiochemical Compound Activity Activity No. (pCa₇₅) (pCa₅₀) 1 +++ +++ 2++ 3 +++ 4 +++ 5 +++ 6 +++ 7 +++ 8 +++ 9 +++ 10 +++ 11 ++ 12 +++ 13 +++14 +++ 15 +++ 16 ++ 17 +++ 21 +++ 22 ++ 24 +++ 25 + 26 +++ 27 +++ +++ 28+++ 29 +++ 30 +++ 31 +++ 32 +++ 33 +++ 34 +++ 35 +++ +++ 36 ++ 37 ++ 38+++ +++ 39 +++ 40 +++ 41 +++ 42 +++ 43 +++ 44 +++ 45 +++ +++ 46 ++ 47 ++48 ++ ++ 49 +++ +++ 50 +++ 51 ++ 52 +++ 53 ++ 54 ++ ++ 55 +++ 56 + 57 ++58 +++ 59 +++ 61 ++ 62 +++ 63 +++ 64 ++ 65 ++ 66 ++ 67 +++ 68 +++ 69 +++++ 70 ++ 71 +++ 72 ++ 73 ++ 74 ++ 75 ++ 76 ++ 77 ++ 78 +++ 79 ++ 80 +++81 ++ 82 +++ +++ 83 +++ 84 +++ 85 +++ 86 ++ 90 ++ 91 ++ 92 ++ ++ 93 +++++ 94 +++ 95 +++ +++ 99 +++ 100 ++ 101 ++ 102 ++ 103 +++ 104 +++ 105 +++106 +++ 107 +++ 108 +++ 109 ++ 110 ++ 111 ++ 112 +++ 113 ++ 114 +++ 115116 +++ 117 +++ 118 +++ 119 +++ 120 +++ 121 +++ 122 ++ 123 +++ 124 +++125 +++ 126 ++ 127 +++ 128 ++ 129 ++ 130 +++ 131 +++ 132 +++ 133 +++ 134+++ 135 +++ 136 +++ 137 +++ ^(a)+++ corresponds to IC50 values below 1uM. ++ corresponds to IC50 values from 1 to 15 uM. + corresponds to IC50values above 15 uM.

Selectivity against rabbit skeletal myofibrils was assessed as describedabove with the exception that the source of myosin was that of fastskeletal myosin from rabbit in the form of myofibrils. Dose responsesagainst rabbit skeletal myofibrils were also determined as describedabove.

Example 74. Stereochemical Reference for Activity

Matched pairs of stereoisomers were tested for their ability to inhibitmyosin activity as described above. The results are summarized in Table3. In all cases, the (R) stereoisomer is significantly less active thanthe (S) stereoisomer.

TABLE 3 Relative activities of (S) and (R) stereoisomers^(a) (S)Stereoisomer (R) Stereoisomer IC50 IC50 IC50 IC50 Cmpd No. (pCa₇₅)(PCa₅₀) Cmpd No (pCa₇₅) (pCa₅₀) 1 0.67 μM 0.56 μM 19R 23.93 μM 51.87 μM21 0.39 μM 20R 19.64 μM 59 0.45 μM 60R >39.2 μM ^(a)assay conductedusing 0.5 μM myosin, therefore IC50 values below 1.0 μM are approximate.

Example 75. Cardiomyocyte Contractility Assay

Contractility of adult rat ventricular myocytes is determined by edgedetection with an IonOptix contractility system. Aliquots of myocytes inTyrode buffer (137 mM NaCl, 3.7 mM KCL, 0.5 mM MgCl₂, 1.5 mM CaCl₂, 4 mMHEPES, 11 mM glucose) are placed in a perfusion chamber (Series 20RC-27NE; Warner Instruments), allowed to adhere to the coverslip, andthen perfused with 37° C. Tyrode buffer. Myocytes are filed stimulatedat 1 Hz and 10V. Only myocytes with clear striations, quiescent prior topacing, with a cell length of 120-180 microns, a basal fractionalshortening equal to 3-8% of the cell length, and a contraction velocitygreater than 100 microns per second are used for contractilityexperiments. To determine the response to compounds, myocytes are firstperfused for 60 seconds with Tyrodes buffer followed by 5 minutes ofcompound and a 140 second washout with Tyrodes buffer. Data iscontinuously recorded using IonOptix software. Contractility data isanalyzed using Ionwizard software (IonOptix). For each cell, 10-20contractility transients were averaged and compared under basal (nocompound) and compound-treated conditions. Compound activity is measuredby effects on fractional shortening (FS), where fractional shortening isthe ratio of the peak length of the cell at contraction divided by thebasal cell length normalized to 100% for an untreated cell.

TABLE 4 Inhibition of Cardiomyocyte Contraction by SelectedCompounds^(a) Activity at 0.3 Activity at 1.0 ID uM uM 1 ++ +++ 2 ++ +++12 n.d. ++ 19 n.d. + 27 ++ n.d. 67 n.d. +++ ^(a)+ represents fractionalshorting inhibition values less than 33%. ++ represents fractionalshorting inhibition values from 33% to 66%. +++ represents fractionalshortening inhibition values greater than 66%.

Example 76. Acute Pharmacodynamic Effect in Rat.

Representative compounds were tested for their ability to modulatecardiac contractility in rat as a measure of in vivo target engagement.Fractional shortening, a measure of contractility, was determined bynoting the change in the diameter of the left ventricle at the end ofsystole/contraction (LVESd) relative to diastole/relaxation (LVEDd) andexpressing this change as the ratio FS=(LVEDd−LVESd)/LVEDd. Fed maleSprague-Dawley rats were lightly anesthetized with isofluorane andbaseline fractional shortening was measured in the parasternal positionusing transthoracic echocardiography (TTE). Following this measurement,animals were recovered and received a single dose of compound (4 mg/kg)by oral gavage. At three hours post-dose, second and thirdechocardiograms were collected under light anesthesia to determine drugeffects on contractility. Effects are represented in Table 5 as apercent reduction of baseline fractional shortening.

TABLE 5 Inhibition of Contractility in Rat by Selected Compounds^(a) %Reduction in Fractional ID Shortening 3 h post-dose 1 +++ 45 + 48 +++ 49+++ 69 + 70 ++ 71 +++ ^(a)+ represents a relative change in fractionalshortening less than 15%. ++ represents a relative change in fractionalshortening between 15-30%. +++ presents a relative change infractionalshortening greater than 30%.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, one of skill in the art will appreciate that certainchanges and modifications may be practiced within the scope of theappended claims. In addition, each reference provided herein isincorporated by reference in its entirety to the same extent as if eachreference was individually incorporated by reference. Where a conflictexists between the instant application and a reference provided herein,the instant application shall dominate.

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein R¹ is a memberselected from the group consisting of C₁-C₈ alkyl, C₃-C₈ cycloalkyl,C₃-C₈ cycloalkyl-C₁-C₄ alkyl, 4- to 7-membered heterocycloalkyl, phenyl,phenyl-C₁-C₄ alkyl, 5- to 6-membered heteroaryl and 5- to 6-memberedheteroaryl-C₁-C₄ alkyl, wherein each R¹ is optionally substituted withfrom 1-3 R^(a); R² is a member selected from the group consisting ofphenyl, phenyl-C₁-C₄ alkyl, 5- to 6-membered heteroaryl and 5- to6-membered heteroaryl-C₁-C₄ alkyl, wherein each R² is optionallysubstituted with from 1-5 R^(b); R³ is a member selected from the groupconsisting of C₁-C₄ alkyl, C₃-C₄ cycloalkyl, and 4- to 7-memberedheterocycloalkyl wherein each R³ is optionally substituted with from 1-3R^(c); R⁴ is H; X is a member selected from the group consisting of Hand F; each R^(a) is independently selected from the group consisting ofhalo, CN, hydroxyl, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenyl,phenyl-C₁-C₄ alkyl, phenyl-C₁-C₄ alkoxy, phenoxy, —COR^(a1), —CO₂R^(a1),—SO₂R^(a1), —SO₂NR^(a1)R^(a2), and —CONR^(a1)R^(a2), wherein each R^(a1)and R^(a2) is independently selected from the group consisting of H,C₁-C₄ alkyl and phenyl, or optionally R^(a1) and R^(a2) when attached toa nitrogen atom are combined to form a 4- to 6-membered ring; each R^(b)is independently selected from the group consisting of halo, CN,hydroxyl, C₁-C₄ alkyl, C₁-C₄ haloalkyl, C₁-C₄ alkoxy, phenoxy,phenyl-C₁-C₄ alkoxy, methylenedioxy, difluoromethylenedioxy, —COR^(b1),—CO₂R^(b1), —SO₂R^(b1), —SO₂NR^(b1)R^(b2), CONR^(b1)R^(b2),NR^(b1)R^(b2), 5- to 6-membered heteroaryl, and 5- to 6-memberedheterocyclyl optionally substituted with oxo, wherein each R^(b1) andR^(b2) is independently selected from the group consisting of H andC₁-C₄ alkyl or optionally R^(b1) and R^(b2) when attached to a nitrogenatom are combined to form a 4- to 6-membered ring; and each RC isindependently selected from the group consisting of halo, hydroxyl andC₁-C₂ alkoxy.
 2. A compound of claim 1, or a pharmaceutically acceptablesalt thereof, wherein, R¹ is a member selected from the group consistingof C₁-C₈ alkyl, C₃-C₈ cycloalkyl, 4- to 7-membered heterocycloalkyl,phenyl, and 5- to 6-membered heteroaryl, wherein each R¹ is optionallysubstituted with from 1-3 R^(a); R² is phenyl, which is optionallysubstituted with from 1-5 R^(b); R³ is a member selected from the groupconsisting of C₁-C₄ alkyl, C₃-C₄ cycloalkyl, and 4- to 7-memberedheterocycloalkyl wherein each R³ is optionally substituted with from 1-2R^(c), R⁴ is H; X is a member selected from the group consisting of Hand F; each R^(a) is independently selected from the group consisting ofhalo, CN, C₁-C₄ alkyl, C₁-C₄ alkoxy, —COR^(a1), —CO₂R^(a1), —SO₂R^(a1),—SO₂NR^(a1)R^(a2), and —CONR^(a1)R^(a2), wherein each R^(a1) and R^(a2)is independently selected from the group consisting of H and C₁-C₄ alkylor optionally R^(a1) and R^(a2) when attached to a nitrogen atom arecombined to form a 4- to 6-membered ring; each R^(b) is independentlyselected from the group consisting of halo, CN, C₁-C₄ alkyl, C₁-C₄alkoxy, —COR^(b1), —CO₂R^(b1), —SO₂R^(b1), —SO₂NR^(b1)R^(b2),CONR^(b1)R^(b2), NR^(b1)R^(b2), 5- to 6-membered heteroaryl, and 5- to6-membered heterocyclyl optionally substituted with oxo, wherein eachR^(b1) and R^(b2) is independently selected from the group consisting ofH and C₁-C₄ alkyl or optionally R^(b1) and R^(b2) when attached to anitrogen atom are combined to form a 4- to 6-membered ring; and eachR^(c) is independently selected from the group consisting of halo andC₁-C₂ alkoxy.
 3. A compound of claim 1 or 2, or a pharmaceuticallyacceptable salt thereof, wherein X is H.
 4. A compound of claim 1 or 2,or a pharmaceutically acceptable salt thereof, wherein R¹ is selectedfrom the group consisting of C₃-C₄ alkyl, C₃-C⁵ cycloalkyl, and 4- to6-membered heterocycloalkyl, wherein each R¹ is optionally substitutedwith from 1-2 R^(a).
 5. A compound of claim 1 or 2, or apharmaceutically acceptable salt thereof, wherein R¹ is selected fromthe group consisting of phenyl and 5- to 6-membered heteroaryl, whereineach R¹ is optionally substituted with from 1-3 R^(a).
 6. A compound ofclaim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R¹is selected from the group consisting of C₃-C₄ alkyl, C₃-C⁵ cycloalkyl,and 4- to 6-membered heterocycloalkyl.
 7. A compound of claim 1 or 2, ora pharmaceutically acceptable salt thereof, wherein R¹ is 4- to6-membered heterocycloalkyl, optionally substituted with from 1-2 R^(a)selected from the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy,—COR^(a1), —CO₂R^(a1), —SO₂R^(a1), —SO₂NR^(a1)R^(a2), and—CONR^(a1)R^(a2), wherein each R^(a1) and R^(a2) is independentlyselected from the group consisting of H and C₁-C₄ alkyl.
 8. A compoundof claim 1 or 2, or a pharmaceutically acceptable salt thereof, whereinR¹ is selected from the group consisting of cyclobutyl, isopropyl,isobutyl, 1-methoxypropan-2-yl, cyclopentyl, cyclohexyl,4-tetrahydropyranyl, 1-(methyl sulfonyl)piperidin-4-yl,1-(methoxycarbonyl)piperidin-4-yl, 4,4-difluorocyclohexyl, phenyl,2-pyridyl, 3-pyridyl, 3-isoxazolyl, 5-isoxazolyl, and1-methyl-3-pyrazolyl.
 9. A compound of claim 1 or 2, or apharmaceutically acceptable salt thereof, wherein R² is optionallysubstituted with from 1-2 R^(b).
 10. A compound of claim 1 or 2, or apharmaceutically acceptable salt thereof, wherein R² is selected fromthe group consisting of phenyl, 3-methylphenyl, 2-fluorophenyl,3-fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,5-difluorophenyl,3-chlorophenyl, 3-methoxyphenyl, 3-(3-oxazolidin-2-onyl)phenyl,3-(2-methyl-1-imidazyl)phenyl, 3-(1-pyrazolyl)phenyl, and3-(1,2,4-triazol-1-yl)phenyl.
 11. A compound of claim 1 or 2, or apharmaceutically acceptable salt thereof, wherein R³ is selected fromthe group consisting of C₁-C₄ alkyl, C¹-C₄ alkoxyalkyl, and C₃-C₄cycloalkyl.
 12. A compound of claim 1 or 2, or a pharmaceuticallyacceptable salt thereof, wherein R³ is selected from the groupconsisting of methyl, ethyl, propyl, cyclopropyl, cyclobutyl and2-methoxymethyl.
 13. A compound of any of claims 1 to 10, or apharmaceutically acceptable salt thereof, wherein R³ is methyl.
 14. Acompound of claim 1 or 2, or a pharmaceutically acceptable salt thereof,wherein R¹ is isopropyl; R² is optionally substituted with 1-2 R^(b);and R³ is methyl.
 15. A compound of claim 1 or 2, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is 4- to 6-memberedheterocycloalkyl, optionally substituted with from 1-2 R^(a) selectedfrom the group consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, —COR_(a1),—CO₂R^(a1), —SO₂R^(a1), —SO₂NR^(a1)R^(a2), and —CONR^(a1)R^(a2), whereineach R^(a1) and R^(a2) is independently selected from the groupconsisting of H and C₁-C₄ alkyl; R² is optionally substituted with 1-2R^(b); and R³ is methyl.
 16. A compound of claim 1 or 2, or apharmaceutically acceptable salt thereof, wherein R¹ is selected fromthe group consisting of phenyl and 5- to 6-membered heteroaryl, whereineach R¹ is optionally substituted with from 1-3 R^(a); R² is optionallysubstituted with from 1-2 R^(b); and R³ is methyl.
 17. A pharmaceuticalcomposition comprising a compound of any of claims 1-16, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 18. A compound of claim 1, selected from the groupconsisting of:

or a pharmaceutically acceptable salt thereof.
 19. A method of treatinghypertrophic cardiomyopathy (HCM), or a cardiac disorder having apathophysiological feature associated with HCM, comprising administeringto a subject in need thereof an effective amount of a compound of any ofclaim 1-16, or 18 or a pharmaceutically acceptable salt thereof.
 20. Amethod of treating a disease or disorder selected from the groupconsisting of diastolic heart failure with preserved ejection fraction,ischemic heart disease, angina pectoris, and restrictive cardiomyopathy,comprising administering to a subject in need thereof an effectiveamount of a compound of any of claim 1-16, or 18 or a pharmaceuticallyacceptable salt thereof.
 21. A method of treating a disease or disordercharacterized by left ventricular hypertrophy due to volume or pressureoverload, said disease or disorder selected from the group consisting ofchronic mitral regurgitation, chronic aortic stenosis, and chronicsystemic hypertension; in conjunction with therapies aimed at correctingor alleviating the primary cause of volume or pressure overload,including valve repair/replacement or effective antihypertensivetherapy, comprising administering to a subject in need thereof aneffective amount of a compound of any of claim 1-16, or 18 or apharmaceutically acceptable salt thereof
 22. A method of treatinghypertrophic cardiomyopathy (HCM), or a cardiac disorder having apathophysiological feature associated with HCM, comprising administeringto a subject in need thereof an effective amount of a compound of any ofclaim 1-16, or 18 or a pharmaceutically acceptable salt thereof combinedwith therapies that retard the progression of heart failure bydown-regulating neurohormonal stimulation of the heart and attempt toprevent cardiac remodeling (e.g., ACE inhibitors, angiotensin receptorblockers (ARBs), β-blockers, aldosterone receptor antagonists, or neuralendopeptidase inhibitors); therapies that improve cardiac function bystimulating cardiac contractility (e.g., positive inotropic agents, suchas the β-adrenergic agonist dobutamine or the phosphodiesteraseinhibitor milrinone); and therapies that reduce cardiac preload (e.g.,diuretics, such as furosemide) or afterload (vasodilators of any class,including but not limited to calcium channel blockers, phosphodiesteraseinhibitors, endothelin receptor antagonists, renin inhibitors, or smoothmuscle myosin modulators).